|
1
|
Nalamachu S, Mallick-Searle T, Adler J, Chan EK, Borgersen W, Lissin D. Multimodal Therapies for the Treatment of Neuropathic Pain: The Role of Lidocaine Patches in Combination Therapy: A Narrative Review. Pain Ther 2025; 14:865-879. [PMID: 40198485 PMCID: PMC12085434 DOI: 10.1007/s40122-025-00733-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 03/18/2025] [Indexed: 04/10/2025] Open
Abstract
Neuropathic pain (NP) has a population presence of up to 10%. Both systemic agents and topical agents are recommended as first-line therapy for the treatment of NP but monotherapy provides adequate pain relief only in < 50% of the cases. This has created the need for multimodal combination therapy, a practice that is becoming more common. Combination therapy with multiple systemic agents has a risk for drug-drug interactions and adverse events (AEs), while add-on therapy with a topical agent such as lidocaine patches minimizes such risks. The focus of this review was to find if there is evidence from trials that combination therapy of the topical lidocaine patches with systemic agents will have better efficacy and/or less risk of AEs than the combination of two systemic agents. Since gabapentinoids are one of the most common systemic agents used in first-line NP therapy, the objective of this review was to summarize the safety and efficacy data and evaluate the benefit-risk ratio from three gabapentinoid combinations; gabapentinoid plus opioids, gabapentinoid plus antidepressants, and gabapentinoid plus topical lidocaine patches. Reviews of clinical trials of combinations of gabapentinoids plus other systemic agents (opioids or antidepressants) were associated with increased AEs and dropouts while improvement in analgesic efficacy was inconsistent. Clinical trials where the patients were provided topical lidocaine patches when their first treatment with a gabapentinoid was inadequate demonstrated improved analgesic efficacy with minimal additional AEs. This led to the conclusion that topical lidocaine patches-associated with minimal systemic adverse effects and proven benefits in various neuropathic pain (NP) conditions-can enhance the likelihood of achieving meaningful pain relief when used as adjuvant therapy for NP.
Collapse
Affiliation(s)
| | | | - Jeremy Adler
- Pacific Pain Medicine Consultants, Oceanside, CA, USA
| | - Elaine K Chan
- Scilex Holding Company, 960 San Antonio Road, Palo Alto, CA, 94303, USA
| | - Wendy Borgersen
- Scilex Holding Company, 960 San Antonio Road, Palo Alto, CA, 94303, USA
| | - Dmitri Lissin
- Scilex Holding Company, 960 San Antonio Road, Palo Alto, CA, 94303, USA.
| |
Collapse
|
|
2
|
Alothman L, Alhadlaq E, Alhussain A, Alabdulkarim A, Sari Y, AlSharari SD. New Pharmacological Insight into Etanercept and Pregabalin in Allodynia and Nociception: Behavioral Studies in a Murine Neuropathic Pain Model. Brain Sci 2024; 14:1145. [PMID: 39595909 PMCID: PMC11591859 DOI: 10.3390/brainsci14111145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/08/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: Neuropathic pain is challenging to treat, often resistant to current therapies, and associated with significant side effects. Pregabalin, an anticonvulsant that modulates calcium channels, is effective but can impair mental and motor functions, especially in older patients. To improve patient outcomes, reducing the doses of pregabalin and combining it with other drugs targeting different neuropathic pain mechanisms may be beneficial. TNF-α blockers such as etanercept have shown potential in addressing neuropathic pain by affecting sodium channels, synaptic transmission, and neuroinflammation. This study evaluates the efficacy and safety of combining low doses of etanercept and pregabalin in allodynia and nociceptive tests. Materials and Methods: Male C57/BL6 mice underwent chronic constriction injury (CCI) of the sciatic nerve to induce neuropathic pain. They were divided into seven groups: sham control, CCI control, low and high doses of pregabalin, low and high doses of etanercept, and a combination of low doses of both drugs. Behavioral tests, including von Frey, hot-plate, and rotarod tests, were used to assess pain responses and motor activity. Results: The results indicated that a high dose of pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia but impaired motor function. Conversely, low doses of etanercept alone had no significant effect. However, the combination of low doses of etanercept (20 mg/kg) and pregabalin (5 mg/kg) effectively alleviated pain without compromising locomotor activity. Conclusions: These results suggest a novel therapeutic strategy for neuropathic pain, enhancing analgesic efficacy while minimizing adverse effects.
Collapse
Affiliation(s)
- Loulwah Alothman
- Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, King Saud University, Riyadh 11451, Saudi Arabia; (E.A.); (A.A.)
| | - Emad Alhadlaq
- Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, King Saud University, Riyadh 11451, Saudi Arabia; (E.A.); (A.A.)
| | - Asma Alhussain
- Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, King Saud University, Riyadh 11451, Saudi Arabia; (E.A.); (A.A.)
| | - Alwaleed Alabdulkarim
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.D.A.)
| | - Youssef Sari
- Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH 43606, USA
| | - Shakir D. AlSharari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia (S.D.A.)
| |
Collapse
|
|
3
|
Upshaw WC, Soileau LG, Storey NR, Perkinson KA, Luther PM, Spillers NJ, Robinson CL, Miller BC, Ahmadzadeh S, Viswanath O, Shekoohi S, Kaye AD. An extract of phase II and III trials on recent developments in managing neuropathic pain syndromes: diabetic peripheral neuropathy, trigeminal neuralgia, and postherpetic neuralgia. Expert Opin Emerg Drugs 2024; 29:103-112. [PMID: 38410863 DOI: 10.1080/14728214.2024.2323193] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/21/2024] [Indexed: 02/28/2024]
Abstract
INTRODUCTION Neuropathic pain (NP) conditions involve lesions to the somatosensory nervous system leading to chronic and debilitating pain. Many patients suffering from NP utilize pharmacological treatments with various drugs that seek to reduce pathologic neuronal states. However, many of these drugs show poor efficacy as well as cause significant adverse effects. Because of this, there is a major need for the development of safer and more efficacious drugs to treat NP. AREAS COVERED In this review, we analyzed current treatments being developed for a variety of NP conditions. Specifically, we sought drugs in phase II/III clinical trials with indications for NP conditions. Various databases were searched including Google Scholar, PubMed, and clinicaltrials.gov. EXPERT OPINION All the mentioned targets for treatments of NP seem to be promising alternatives for existing treatments that often possess poor side effect profiles for patients. However, gene therapy potentially offers the unique ability to inject a plasmid containing growth factors leading to nerve growth and repair. Because of this, gene therapy appears to be the most intriguing new treatment for NP.
Collapse
Affiliation(s)
- William C Upshaw
- School of Medicine, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Lenise G Soileau
- School of Medicine, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Nicholas R Storey
- School of Medicine, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | | | - Patrick M Luther
- School of Medicine, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Noah J Spillers
- School of Medicine, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Christopher L Robinson
- Beth Israel Deaconess Medical Center, Department of Anesthesiology, Critical Care, and Pain Medicine, Harvard Medical School, Boston, MA, USA
| | - Benjamin C Miller
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, USA
| | - Shahab Ahmadzadeh
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, USA
| | - Omar Viswanath
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, USA
- Creighton University School of Medicine, Phoenix, AZ, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, USA
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, USA
| |
Collapse
|
|
4
|
Frisaldi E, Vollert J, Al Sultani H, Benedetti F, Shaibani A. Placebo and nocebo responses in painful diabetic neuropathy: systematic review and meta-analysis. Pain 2024; 165:29-43. [PMID: 37530658 DOI: 10.1097/j.pain.0000000000003000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 06/08/2023] [Indexed: 08/03/2023]
Abstract
ABSTRACT This preregistered (CRD42021223379) systematic review and meta-analysis aimed to characterize the placebo and nocebo responses in placebo-controlled randomized clinical trials (RCTs) on painful diabetic neuropathy (PDN), updating the previous literature by a decade. Four databases were searched for PDN trials published in the past 20 years, testing oral medications, adopting a parallel-group design. Magnitude of placebo or nocebo responses, Cochrane risk of bias, heterogeneity, and moderators were evaluated. Searches identified 21 studies (2425 placebo-treated patients). The overall mean pooled placebo response was -1.54 change in the pain intensity from baseline [95% confidence interval (CI): -1.52, -1.56, I 2 = 72], with a moderate effect size (Cohen d = 0.72). The pooled placebo 50% response rate was 25% [95% CI: 22, 29, I 2 = 50%]. The overall percentage of patients with adverse events (AEs) in the placebo arms was 53.3% [95% CI: 50.9, 55.7], with 5.1% [95% CI: 4.2, 6] of patients dropping out due to AEs. The year of study initiation was the only significant moderator of placebo response (regression coefficient = -0.06, [95% CI: -0.10, -0.02, P = 0.007]). More recent RCTs tended to be longer, bigger, and to include older patients (N = 21, rs = 0.455, P = 0.038, rs = 0.600, P = 0.004, rs = 0.472, P = 0.031, respectively). Our findings confirm the magnitude of placebo and nocebo responses, identify the year of study initiation as the only significant moderator of placebo response, draw attention to contextual factors such as confidence in PDN treatments, patients' previous negative experiences, intervention duration, and information provided to patients before enrollment.
Collapse
Affiliation(s)
- Elisa Frisaldi
- Rita Levi Montalcini Department of Neuroscience, University of Turin Medical School, Turin, Italy
| | - Jan Vollert
- Pain Research, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Muenster, Germany
- Neurophysiology, Mannheim Center of Translational Neuroscience (MCTN), Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | | | - Fabrizio Benedetti
- Rita Levi Montalcini Department of Neuroscience, University of Turin Medical School, Turin, Italy
- Medicine and Physiology of Hypoxia, Plateau Rosà, Switzerland
| | - Aziz Shaibani
- Nerve and Muscle Center of Texas, Houston, TX, United States
- Baylor College of Medicine, Houston, TX, United States
| |
Collapse
|
|
5
|
Boccella S, De Filippis L, Giorgio C, Brandolini L, Jones M, Novelli R, Amorizzo E, Leoni MLG, Terranova G, Maione S, Luongo L, Leone M, Allegretti M, Minnella EM, Aramini A. Combination Drug Therapy for the Management of Chronic Neuropathic Pain. Biomolecules 2023; 13:1802. [PMID: 38136672 PMCID: PMC10741625 DOI: 10.3390/biom13121802] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/01/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation. However, while preclinical studies with combination therapies showed promise to improve efficacy over monotherapy, clinical trial data on their efficacy in specific populations are lacking and increased risk for adverse effects should be carefully considered. Drug-drug co-crystallization has emerged as an innovative pharmacological approach which can combine two or more different active pharmaceutical ingredients in a single crystal, optimizing pharmacokinetic and physicochemical characteristics of the native molecules, thus potentially capitalizing on the synergistic efficacy between classes of drugs while simplifying adherence and minimizing the risk of side effects by reducing the doses. In this work, we review the current pharmacological options for the treatment of chronic NP, focusing on combination therapies and their ongoing developing programs and highlighting the potential of co-crystals as novel approaches to chronic NP management.
Collapse
Affiliation(s)
- Serena Boccella
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via De Amicis, 80131 Naples, Italy; (S.B.); (C.G.)
| | - Lidia De Filippis
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via S. Lucia, 20122 Milan, Italy; (L.D.F.); (R.N.); (M.L.); (E.M.M.)
| | - Cristina Giorgio
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via De Amicis, 80131 Naples, Italy; (S.B.); (C.G.)
| | - Laura Brandolini
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via Campo di Pile, 67100 L’Aquila, Italy; (L.B.); (M.A.)
| | - Meghan Jones
- Research & Early Development (R&D), Dompé US, 181 2nd Avenue, STE 600, San Mateo, CA 94401, USA;
| | - Rubina Novelli
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via S. Lucia, 20122 Milan, Italy; (L.D.F.); (R.N.); (M.L.); (E.M.M.)
| | - Ezio Amorizzo
- Pain Unit, San Paolo Hospital, 00053 Civitavecchia, Italy;
- Pain Clinic Roma, 00191 Rome, Italy
| | - Matteo Luigi Giuseppe Leoni
- Azienda USL di Piacenza, 29121 Piacenza, Italy;
- Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University, 00185 Rome, Italy
| | | | - Sabatino Maione
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.M.); (L.L.)
| | - Livio Luongo
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (S.M.); (L.L.)
| | - Manuela Leone
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via S. Lucia, 20122 Milan, Italy; (L.D.F.); (R.N.); (M.L.); (E.M.M.)
| | - Marcello Allegretti
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via Campo di Pile, 67100 L’Aquila, Italy; (L.B.); (M.A.)
| | - Enrico Maria Minnella
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via S. Lucia, 20122 Milan, Italy; (L.D.F.); (R.N.); (M.L.); (E.M.M.)
| | - Andrea Aramini
- Research & Early Development (R&D), Dompé Farmaceutici S.p.A, Via Campo di Pile, 67100 L’Aquila, Italy; (L.B.); (M.A.)
| |
Collapse
|
|
6
|
Essmat N, Galambos AR, Lakatos PP, Karádi DÁ, Mohammadzadeh A, Abbood SK, Geda O, Laufer R, Király K, Riba P, Zádori ZS, Szökő É, Tábi T, Al-Khrasani M. Pregabalin-Tolperisone Combination to Treat Neuropathic Pain: Improved Analgesia and Reduced Side Effects in Rats. Pharmaceuticals (Basel) 2023; 16:1115. [PMID: 37631030 PMCID: PMC10459435 DOI: 10.3390/ph16081115] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
The current treatment of neuropathic pain (NP) is unsatisfactory; therefore, effective novel agents or combination-based analgesic therapies are needed. Herein, oral tolperisone, pregabalin, and duloxetine were tested for their antinociceptive effect against rat partial sciatic nerve ligation (pSNL)-induced tactile allodynia described by a decrease in the paw withdrawal threshold (PWT) measured by a dynamic plantar aesthesiometer. On day 7 after the operation, PWTs were assessed at 60, 120, and 180 min post-treatment. Chronic treatment was continued for 2 weeks, and again, PWTs were measured on day 14 and 21. None of the test compounds produced an acute antiallodynic effect. In contrast, after chronic treatment, tolperisone and pregabalin alleviated allodynia. In other experiments, on day 14, the acute antiallodynic effect of the tolperisone/pregabalin or duloxetine combination was measured. As a novel finding, a single dose of the tolperisone/pregabalin combination could remarkably alleviate allodynia acutely. It also restored the neuropathy-induced elevated CSF glutamate content. Furthermore, the combination is devoid of adverse effects related to motor and gastrointestinal transit functions. Tolperisone and pregabalin target voltage-gated sodium and calcium channels, respectively. The dual blockade effect of the combination might explain its advantageous acute analgesic effect in the present work.
Collapse
Affiliation(s)
- Nariman Essmat
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Anna Rita Galambos
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
| | - Péter P. Lakatos
- Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (P.P.L.); (O.G.); (R.L.); (É.S.)
| | - Dávid Árpád Karádi
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
| | - Amir Mohammadzadeh
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
| | - Sarah Kadhim Abbood
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
| | - Orsolya Geda
- Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (P.P.L.); (O.G.); (R.L.); (É.S.)
| | - Rudolf Laufer
- Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (P.P.L.); (O.G.); (R.L.); (É.S.)
| | - Kornél Király
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
| | - Pál Riba
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
| | - Zoltán S. Zádori
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
| | - Éva Szökő
- Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (P.P.L.); (O.G.); (R.L.); (É.S.)
| | - Tamás Tábi
- Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (P.P.L.); (O.G.); (R.L.); (É.S.)
| | - Mahmoud Al-Khrasani
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, H-1089 Budapest, Hungary; (N.E.); (A.R.G.); (D.Á.K.); (A.M.); (S.K.A.); (K.K.); (P.R.); (Z.S.Z.)
| |
Collapse
|
|
7
|
K. K, Dutt S, Rattan P, Dadhania A, Gupta R, Joshi D, Kakkad A, Makwana A, Jha P. Fixed dose combination of low dose pregabalin and duloxetine, or pregabalin monotherapy for neuropathic pain: A double-blind, randomized, parallel-group study. F1000Res 2023; 12:353. [PMID: 38618021 PMCID: PMC11016171 DOI: 10.12688/f1000research.130345.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/13/2023] [Indexed: 04/16/2024] Open
Abstract
Background: Treatment of neuropathic pain is challenging. Pregabalin and duloxetine are used as first-line therapy. Various international guidelines recommend a combination of first-line agents for the management of neuropathic pain. The objective of this study was to evaluate the efficacy and safety of a fixed-dose combination (FDC) of low-dose pregabalin and duloxetine compared to pregabalin monotherapy at week 7 in patients with moderate to severe neuropathic pain. Methods: This was a phase 3, randomized, double-blind, double-dummy parallel-group non-inferiority study conducted at 17 sites across India. Three hundred and twenty-eight adult patients with moderate to severe neuropathic pain were randomized in a ratio of 1:1 to receive a FDC of pregabalin and duloxetine or pregabalin monotherapy for 7 weeks followed by a one-week follow-up. The pregabalin-duloxetine combination was initiated at 50 plus 20 mg per day and gradually titrated to a maximum of 75mg plus 30mg twice daily. Pregabalin was initiated at 75mg/day and gradually titrated to a maximum of 150mg twice daily. The main efficacy outcome was a mean change in pain intensity at the end of 7 weeks. Results: Two hundred and ninety-eight patients completed the study, 148 in the pregabalin-duloxetine group and 150 in the pregabalin group. The mean change in daily pain at 7 weeks was as follows: -4.49 with FDC and -4.66 with pregabalin (p<0.0001). The non-inferiority of a low-dose FDC compared to pregabalin monotherapy was demonstrated at the end of the study. The incidence of dizziness and somnolence was comparable between both treatments. A higher frequency of peripheral oedema was observed with pregabalin monotherapy than in the FDC group (p>0.05). Conclusions: A FDC of low doses of pregabalin and duloxetine and high dose of pregabalin monotherapy achieved similar analgesia with dizziness, and somnolence as the most frequent adverse event. Trial registration: CTRI/2020/09/027555.
Collapse
Affiliation(s)
- Krishnaprasad K.
- Medical Services, Torrent Pharmaceuticals Limited, Gandhinagar, Gujrat, 382428, India
| | - Sunil Dutt
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Pankaj Rattan
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Ankit Dadhania
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Ram Gupta
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Deepa Joshi
- Torrent Pharmaceuticals Limited, Torrent Research Center, Bhat, Gandhinagar, Gujarat, 382428, India
| | - Ashutosh Kakkad
- Medical Services, Torrent Pharmaceuticals Limited, Gandhinagar, Gujrat, 382428, India
| | - Altaf Makwana
- Medical Services, Torrent Pharmaceuticals Limited, Gandhinagar, Gujrat, 382428, India
| | - Pankaj Jha
- Medical Services, Torrent Pharmaceuticals Limited, Gandhinagar, Gujrat, 382428, India
| |
Collapse
|
|
8
|
Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis. Pain 2023; 164:230-251. [PMID: 35588148 DOI: 10.1097/j.pain.0000000000002688] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023]
Abstract
ABSTRACT Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. More than half of patients receive 2 or more analgesics, and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind randomized controlled trials evaluating combinations of 2 or more drugs vs placebo or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects. Risk of bias was assessed. Meta-analyses compared combination to monotherapy wherever 2 or more similar studies were available. Forty studies (4741 participants) were included. Studies were heterogenous with respect to various characteristics, including dose titration methods and administration (ie, simultaneous vs sequential) of the combination. Few combinations involved a nonsedating drug, and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid, and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared with monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy-as second- or third-line treatment-in situations where monotherapy is insufficient, should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving nonsedating agents, and to identify clinical settings and specific combinations that safely provide added benefit.
Collapse
|
|
9
|
Yaseen B, Gangwar C, Nayak R, Kumar S, Sarkar J, Banerjee M, Mohan Naik R. Gabapentin loaded silver nanoparticles (GBP@AgNPs) for its promising biomedical application as a nanodrug: Anticancer and Antimicrobial activities. INORG CHEM COMMUN 2022. [DOI: 10.1016/j.inoche.2022.110380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
10
|
Chen HY, Wang ZN, Zhang WY, Zhu T. Advances in the clinical application of oxycodone in the perioperative period. World J Clin Cases 2022; 10:5156-5164. [PMID: 35812649 PMCID: PMC9210879 DOI: 10.12998/wjcc.v10.i16.5156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/29/2022] [Accepted: 04/03/2022] [Indexed: 02/06/2023] Open
Abstract
To review the research progress of pure opioid receptor agonist oxycodone. The research progress of oxycodone in terms of pharmacokinetics, pharmacodynamics, adverse reactions, clinical application, combined medication and new progress in clinical application was summarized by referring to the literature. Oxycodone is a semi-synthetic thebaine derivative of opioid alkaloids, and is a pure opioid μ and κ receptor agonist. The main action sites are the central nervous system and visceral smooth muscle. Due to its advantages of low adverse reactions, good analgesic effects, and a wide range of safe doses, the drug has been widely used in the control of acute and chronic postoperative pain, as well as malignant and non-malignant pain. Since the end of the 20th century, researchers have begun to formulate antipyretic analgesics, opioid receptor agonists, opioid receptor antagonists, dopamine receptor antagonists and other drugs with oxycodone in different proportions to enhance the analgesic effect. At the same time, it can reduce the dosage of oxycodone and reduce its adverse reactions, so as to achieve the purpose of limiting opioid abuse. With the continuous research on the efficacy and safety of oxycodone in the perioperative period at home and abroad, oxycodone has become the only dual-opioid potent analgesic that can be used in clinical work.
Collapse
Affiliation(s)
- Hong-Yang Chen
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- The Research Units of West China(2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zi-Ning Wang
- Department of Anesthesiology, West China School of Clinical Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wei-Yi Zhang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- The Research Units of West China(2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Tao Zhu
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- The Research Units of West China(2018RU012)-Chinese Academy of Medical Sciences, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| |
Collapse
|
|
11
|
Chen C, Winterstein AG, Lo-Ciganic WH, Tighe PJ, Wei YJJ. Concurrent use of prescription gabapentinoids with opioids and risk for fall-related injury among older US Medicare beneficiaries with chronic noncancer pain: A population-based cohort study. PLoS Med 2022; 19:e1003921. [PMID: 35231025 PMCID: PMC8887769 DOI: 10.1371/journal.pmed.1003921] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 01/19/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Gabapentinoids are increasingly prescribed to manage chronic noncancer pain (CNCP) in older adults. When used concurrently with opioids, gabapentinoids may potentiate central nervous system (CNS) depression and increase the risks for fall. We aimed to investigate whether concurrent use of gabapentinoids with opioids compared with use of opioids alone is associated with an increased risk of fall-related injury among older adults with CNCP. METHODS AND FINDINGS We conducted a population-based cohort study using a 5% national sample of Medicare beneficiaries in the United States between 2011 and 2018. Study sample consisted of fee-for-service (FFS) beneficiaries aged ≥65 years with CNCP diagnosis who initiated opioids. We identified concurrent users with gabapentinoids and opioids days' supply overlapping for ≥1 day and designated first day of concurrency as the index date. We created 2 cohorts based on whether concurrent users initiated gabapentinoids on the day of opioid initiation (Cohort 1) or after opioid initiation (Cohort 2). Each concurrent user was matched to up to 4 opioid-only users on opioid initiation date and index date using risk set sampling. We followed patients from index date to first fall-related injury event ascertained using a validated claims-based algorithm, treatment discontinuation or switching, death, Medicare disenrollment, hospitalization or nursing home admission, or end of study, whichever occurred first. In each cohort, we used propensity score (PS) weighted Cox models to estimate the adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of fall-related injury, adjusting for year of the index date, sociodemographics, types of chronic pain, comorbidities, frailty, polypharmacy, healthcare utilization, use of nonopioid medications, and opioid use on and before the index date. We identified 6,733 concurrent users and 27,092 matched opioid-only users in Cohort 1 and 5,709 concurrent users and 22,388 matched opioid-only users in Cohort 2. The incidence rate of fall-related injury was 24.5 per 100 person-years during follow-up (median, 9 days; interquartile range [IQR], 5 to 18 days) in Cohort 1 and was 18.0 per 100 person-years during follow-up (median, 9 days; IQR, 4 to 22 days) in Cohort 2. Concurrent users had similar risk of fall-related injury as opioid-only users in Cohort 1(aHR = 0.97, 95% CI 0.71 to 1.34, p = 0.874), but had higher risk for fall-related injury than opioid-only users in Cohort 2 (aHR = 1.69, 95% CI 1.17 to 2.44, p = 0.005). Limitations of this study included confounding due to unmeasured factors, unavailable information on gabapentinoids' indication, potential misclassification, and limited generalizability beyond older adults insured by Medicare FFS program. CONCLUSIONS In this sample of older Medicare beneficiaries with CNCP, initiating gabapentinoids and opioids simultaneously compared with initiating opioids only was not significantly associated with risk for fall-related injury. However, addition of gabapentinoids to an existing opioid regimen was associated with increased risks for fall. Mechanisms for the observed excess risk, whether pharmacological or because of channeling of combination therapy to high-risk patients, require further investigation. Clinicians should consider the risk-benefit of combination therapy when prescribing gabapentinoids concurrently with opioids.
Collapse
Affiliation(s)
- Cheng Chen
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, United States of America
| | - Almut G. Winterstein
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, United States of America
- Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, United States of America
- Department of Epidemiology, University of Florida Colleges of Medicine and Public Health & Health Professions, Florida, United States of America
| | - Wei-Hsuan Lo-Ciganic
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, United States of America
- Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, United States of America
| | - Patrick J. Tighe
- Department of Anesthesiology, University of Florida College of Medicine, Florida, United States of America
| | - Yu-Jung Jenny Wei
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, United States of America
- Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, United States of America
- * E-mail:
| |
Collapse
|
|
12
|
Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain. Pharmaceuticals (Basel) 2022; 15:ph15010088. [PMID: 35056145 PMCID: PMC8780738 DOI: 10.3390/ph15010088] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 02/05/2023] Open
Abstract
Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. The new gabapentinoid, mirogabalin has recently been approved for clinical use. Although its main mechanism of action occurs at the α2σ-1 and α2σ-2 subunits of calcium channels and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level has not been clarified, which is crucial information from a clinical perspective. The findings of our study suggest that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This is the first study to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the concentration of the pronociceptive substance P. Importantly, mirogabalin improves the morphine-, buprenorphine-, oxycodone-, and ketamine-induced antinociceptive effects in a neuropathic pain model. Our findings support the hypothesis that enhancing opioid and ketamine analgesia by combining these drugs with mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.
Collapse
|
|
13
|
Sloan G, Alam U, Selvarajah D, Tesfaye S. The Treatment of Painful Diabetic Neuropathy. Curr Diabetes Rev 2022; 18:e070721194556. [PMID: 34238163 DOI: 10.2174/1573399817666210707112413] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/18/2021] [Accepted: 03/08/2021] [Indexed: 11/22/2022]
Abstract
Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.
Collapse
Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine and the Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, and Liverpool University Hospital, NHS Foundation Trust, Liverpool, UK
- Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| |
Collapse
|
|
14
|
Aljassem A, Hall LM, Spickler M, Menkes DL. A Practical Approach to the Treatment of Painful Polyneuropathies. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00006-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
|
15
|
Wallace MS. Effect of Pregabalin on the Median Effective Plasma Concentration of Intravenous Alfentanil in Capsaicin-Induced Pain. PAIN MEDICINE 2021; 22:3072-3079. [PMID: 34329455 DOI: 10.1093/pm/pnab222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVE To apply the sequential up-down method to a human experimental pain model in order to examine the opioid-sparing effect of oral pregabalin on intravenous alfentanil. DESIGN Double-blind, randomized, crossover. SETTING Academic university medical center. SUBJECTS Thirty-one healthy males. METHODS The median effective plasma concentration of intravenous alfentanil was determined under two conditions: alfentanil alone (phase I) and alfentanil+ pregabalin (300 mg orally) (phase II). The alfentanil plasma level (after a computer-controlled infusion) producing a success criterion (at least 30% intradermal capsaicin-induced pain reduction compared with placebo) was used to determine higher or lower doses for each sequential subject. The median dose producing a success criterion and its confidence interval were determined. RESULTS On the basis of the t test for a difference across phase and regression coefficients across groups, there was no opioid-sparing effect of pregabalin on alfentanil. Four subjects in phase I and five subjects in phase II did not complete the study. Two in phase I were technical failures, with the rest in both phases stopped because of side effects. Of the subjects who completed the study, six of 19 subjects in phase I and 11 of 12 subjects in phase II reported side effects. CONCLUSIONS When the intradermal capsaicin-induced pain model was used in healthy volunteers, oral pregabalin had no opioid-sparing effects on intravenous alfentanil. This experimental model may be useful in studying analgesic interactions.
Collapse
Affiliation(s)
- Mark S Wallace
- Division of Pain Medicine, Department of Anesthesiology, University of California, La Jolla, California, USA
| |
Collapse
|
|
16
|
Romanelli MN, Borgonetti V, Galeotti N. Dual BET/HDAC inhibition to relieve neuropathic pain: Recent advances, perspectives, and future opportunities. Pharmacol Res 2021; 173:105901. [PMID: 34547384 DOI: 10.1016/j.phrs.2021.105901] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/03/2021] [Accepted: 09/14/2021] [Indexed: 12/15/2022]
Abstract
Despite the intense research on developing new therapies for neuropathic pain states, available treatments have limited efficacy and unfavorable safety profiles. Epigenetic alterations have a great influence on the development of cancer and neurological diseases, as well as neuropathic pain. Histone acetylation has prevailed as one of the well investigated epigenetic modifications in these diseases. Altered spinal activity of histone deacetylase (HDAC) and Bromo and Extra terminal domain (BET) have been described in neuropathic pain models and restoration of these aberrant epigenetic modifications showed pain-relieving activity. Over the last decades HDACs and BETs have been the focus of drug discovery studies, leading to the development of numerous small-molecule inhibitors. Clinical trials to evaluate their anticancer activity showed good efficacy but raised toxicity concerns that limited translation to the clinic. To maximize activity and minimize toxicity, these compounds can be applied in combination of sub-maximal doses to produce additive or synergistic interactions (combination therapy). Recently, of particular interest, dual BET/HDAC inhibitors (multi-target drugs) have been developed to assure simultaneous modulation of BET and HDAC activity by a single molecule. This review will summarize the most recent advances with these strategies, describing advantages and limitations of single drug treatment vs combination regimens. This review will also provide a focus on dual BET/HDAC drug discovery investigations as future therapeutic opportunity for human therapy of neuropathic pain.
Collapse
Affiliation(s)
- Maria Novella Romanelli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy
| | - Vittoria Borgonetti
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
| | - Nicoletta Galeotti
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology and Toxicology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
| |
Collapse
|
|
17
|
Pafili K, Papanas N. Considerations for single- versus multiple-drug pharmacotherapy in the management of painful diabetic neuropathy. Expert Opin Pharmacother 2021; 22:2267-2280. [PMID: 33819123 DOI: 10.1080/14656566.2021.1909570] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION The efficacy of monotherapy to reduce pain from diabetic peripheral neuropathy (DPN) is frequently not satisfactory and guidelines do not provide unanimous treatment options. In this context, multiple drug pharmacotherapy may provide benefit. AREAS COVERED The aim of the present review is to describe the clinical trials addressing the pharmacotherapy of painful DPN. Studies discussing efficacy and tolerability of pharmacological agents that were assessed in monotherapy and in combination treatment are reported and discussed. EXPERT OPINION Several clinical trials have reported benefit of multiple-drug pharmacotherapy. Nevertheless, untoward effects of combination treatment are of concern. Importantly, some trials were restricted to comparison with placebo and other compared only with active comparator(s). Only limited clinical trials assessed selected cohorts of individuals experiencing different stages of painful DPN. Despite current limitations, some evidence of studies implicating a comparison to all active comparators points to safety and effectiveness of the combination of oxycodone with pregabalin and that of pregabalin with the 5% lidocaine plaster but future, clear-cut studies are required to drive evidence-based decisions in the clinical setting.
Collapse
Affiliation(s)
- Kalliopi Pafili
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| |
Collapse
|
|
18
|
Roy PJ, Weltman M, Dember LM, Liebschutz J, Jhamb M. Pain management in patients with chronic kidney disease and end-stage kidney disease. Curr Opin Nephrol Hypertens 2020; 29:671-680. [PMID: 32941189 PMCID: PMC7753951 DOI: 10.1097/mnh.0000000000000646] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW This review evaluates current recommendations for pain management in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) with a specific focus on evidence for opioid analgesia, including the partial agonist, buprenorphine. RECENT FINDINGS Recent evidence supports the use of physical activity and other nonpharmacologic therapies, either alone or with pharmacological therapies, for pain management. Nonopioid analgesics, including acetaminophen, topical analgesics, gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and TCA may be considered based on pain cause and type, with careful dose considerations in kidney disease. NSAIDs may be used in CKD and ESKD for short durations with careful monitoring. Opioid use should be minimized and reserved for patients who have failed other therapies. Opioids have been associated with increased adverse events in this population, and thus should be used cautiously after risk/benefit discussion with the patient. Opioids that are safer to use in kidney disease include oxycodone, hydromorphone, fentanyl, methadone, and buprenorphine. Buprenorphine appears to be a promising and safer option due to its partial agonism at the mu opioid receptor. SUMMARY Pain is poorly managed in patients with kidney disease. Nonpharmacological and nonopioid analgesics should be first-line approaches for pain management. Opioid use should be minimized with careful monitoring and dose adjustment.
Collapse
Affiliation(s)
- Payel Jhoom Roy
- Division of General Internal Medicine, Department of Medicine, University of Pittsburgh School of Medicine
| | - Melanie Weltman
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy
| | - Laura M. Dember
- Renal, Electrolyte and Hypertension Division, Department of Medicine, and Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine
| | - Jane Liebschutz
- Division of General Internal Medicine, Department of Medicine, University of Pittsburgh School of Medicine
| | - Manisha Jhamb
- Division of Renal-Electrolyte, Department of Medicine, University of Pittsburgh
| |
Collapse
|
|
19
|
Li D, Yoo JH, Kim SK. Long-Lasting and Additive Analgesic Effects of Combined Treatment of Bee Venom Acupuncture and Venlafaxine on Paclitaxel-Induced Allodynia in Mice. Toxins (Basel) 2020; 12:toxins12100620. [PMID: 32998357 PMCID: PMC7600305 DOI: 10.3390/toxins12100620] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/18/2020] [Accepted: 09/25/2020] [Indexed: 12/11/2022] Open
Abstract
Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg; VLX, 60 mg/kg). Spinal pre-administration of idazoxan (α2-adrenergic receptor antagonist, 10 μg), methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 10 μg), or MDL-72222 (5-HT3 receptor antagonist, 10 μg) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy.
Collapse
Affiliation(s)
- Daxian Li
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea;
| | - Ju Hyuk Yoo
- Department of East-West Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea;
| | - Sun Kwang Kim
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea;
- Department of East-West Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea;
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
- Correspondence:
| |
Collapse
|
|
20
|
|
|
21
|
Alam U, Sloan G, Tesfaye S. Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs. Drugs 2020; 80:363-384. [DOI: 10.1007/s40265-020-01259-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
|
|
22
|
Buttram ME, Kurtz SP, Cicero TJ, Havens JR. An ethnographic decision model of the initiation of gabapentin misuse among prescription and/or illicit opioid (mis)user. Drug Alcohol Depend 2019; 204:107554. [PMID: 31542629 PMCID: PMC6905052 DOI: 10.1016/j.drugalcdep.2019.107554] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/08/2019] [Accepted: 07/09/2019] [Indexed: 01/21/2023]
Abstract
AIMS Gabapentin is used in the treatment of seizures and neuralgia, and it is prescribed off-label to treat substance use disorders and withdrawal symptoms. Recent research documents misuse of gabapentin, especially among prescription opioid misusers. The present study contributes to this literature by examining the initiation of gabapentin misuse. METHODS Qualitative interviews were conducted with prescription and/or illicit opioid (mis)users who reported a history of gabapentin misuse (N = 62) and who did not (N = 29). During semi-structured interviews, respondents provided descriptions of the first time they misused gabapentin. An ethnographic decision model was constructed to illustrate the factors that influence the initiation decision. RESULTS Multiple individual, social, and environmental factors influence the decision to initiate gabapentin misuse. Respondents described the initiation decision related to: a) wanting to feel a psychoactive high during times of limited access to one's preferred drug because of institutional barriers (e.g., substance abuse treatment; jail; transitional living facility; N = 18); b) the desire to use multiple drugs, including for experimentation or to potentiate another substance (N = 18); and c) the need to self-treat withdrawal symptoms during periods of opioid nonuse or when opioids were unavailable (N = 16). Respondents also initiated gabapentin misuse to self-treat physical pain (N = 10). CONCLUSIONS Multiple approaches are needed to mitigate gabapentin misuse, including limiting availability in institutional settings and informal channels as well as addressing the needs of drug users who experience physical pain and withdrawal symptoms. Continued research is needed to examine therapeutic uses of gabapentin and behaviors related to misuse.
Collapse
Affiliation(s)
- Mance E. Buttram
- ARSH: Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, 7255 NE 4th Ave., Suite 112, Miami, FL 33138 USA
| | - Steven P. Kurtz
- ARSH: Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, 7255 NE 4th Ave., Suite 112, Miami, FL 33138 USA
| | - Theodore J. Cicero
- Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave., Box 8134, St. Louis, MO 63110 USA
| | - Jennifer R. Havens
- Department of Behavioral Science, University of Kentucky, 333 Waller Ave., Suite 480, Lexington, KY 40504 USA
| |
Collapse
|
|
23
|
Franz S, Schulz B, Wang H, Gottschalk S, Grüter F, Friedrich J, Glaesener JJ, Bock F, Schott C, Müller R, Schultes K, Landmann G, Gerner HJ, Dietz V, Treede RD, Weidner N. Management of pain in individuals with spinal cord injury: Guideline of the German-Speaking Medical Society for Spinal Cord Injury. GERMAN MEDICAL SCIENCE : GMS E-JOURNAL 2019; 17:Doc05. [PMID: 31354397 PMCID: PMC6637293 DOI: 10.3205/000271] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Indexed: 12/19/2022]
Abstract
Introduction: Pain is a prominent complication in spinal cord injury (SCI). It can either occur as a direct or as an indirect consequence of SCI and it often heavily influences the quality of life of affected individuals. In SCI, nociceptive and neuropathic pain can equally emerge at the same time above or below the level of injury. Thus, classification and grading of pain is frequently difficult. Effective treatment of SCI-related pain in general and of neuropathic pain in particular is challenging. Current treatment options are sparse and their evidence is considered to be limited. Considering these aspects, a clinical practice guideline was developed as basis for an optimized, comprehensive and standardized pain management in SCI-related pain. Methods: The German-Speaking Medical Society for Spinal Cord Injury (Deutschsprachige Medizinische Gesellschaft für Paraplegiologie – DMGP) developed a clinical practice guideline that received consensus from seven further German-speaking medical societies and one patient organization. The evidence base from clinical trials and meta-analyses was summarized and subjected to a structured consensus-process in accordance with the regulations of the Association of Scientific Medical Societies in Germany (AWMF) and the methodological requirements of the “German instrument for methodological guideline appraisal”. Results: This consensus-based guideline (S2k classification according to the AWMF guidance manual and rules) resulted in seven on-topic statements and 17 specific recommendations relevant to the classification, assessment and therapy of pain directly or indirectly caused by SCI. Recommended therapeutic approaches comprise pharmacological (e.g. nonsteroidal anti-inflammatory drugs or anticonvulsants) and non-pharmacological (e.g. physical activity or psychotherapeutic techniques) strategies for both nociceptive and neuropathic pain. Discussion: Assessment of SCI-related pain is standardized and respective methods in terms of examination, classification and grading of pain are already in use and validated in German language. In contrast, valid, evidence-based and efficient therapeutic options are limited and ask for further clinical studies, ideally randomized controlled trials and meta-analyses.
Collapse
Affiliation(s)
- Steffen Franz
- Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
| | - Barbara Schulz
- BG Klinikum Bergmannstrost, Abteilung Medizinische Psychologie, Spezielle Traumatherapie (DeGPT), Hypnotherapie und Hypnose (DGH), Halle, Germany
| | - Haili Wang
- Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
| | - Sabine Gottschalk
- Zentralklinik Bad Berka GmbH, Querschnittgelähmten-Zentrum/Klinik für Paraplegiologie und Neuro-Urologie, Bad Berka, Germany
| | - Florian Grüter
- Kliniken Beelitz GmbH, Neurologische Rehabilitationsklinik, Beelitz-Heilstätten, Germany
| | | | | | | | - Cordelia Schott
- Orthopädische Privatpraxis Schott (OPS), Im Medizinischen Zentrum Essen, Germany
| | | | - Kevin Schultes
- Fördergemeinschaft der Querschnittgelähmten in Deutschland e.V., Lobbach, Germany
| | - Gunther Landmann
- Center for Pain Medicine, Swiss Paraplegic Centre, Nottwil, Switzerland
| | - Hans Jürgen Gerner
- Fördergemeinschaft der Querschnittgelähmten in Deutschland e.V., Lobbach, Germany
| | - Volker Dietz
- Spinal Cord Injury Center, University Hospital Balgrist, Zurich, Switzerland
| | - Rolf-Detlef Treede
- Chair of Neurophysiology, Centre of Biomedicine and Medical Technology Mannheim, Heidelberg University, Mannheim, Germany
| | - Norbert Weidner
- Spinal Cord Injury Center, Heidelberg University Hospital, Heidelberg, Germany
| |
Collapse
|
|
24
|
Bates D, Schultheis BC, Hanes MC, Jolly SM, Chakravarthy KV, Deer TR, Levy RM, Hunter CW. A Comprehensive Algorithm for Management of Neuropathic Pain. PAIN MEDICINE (MALDEN, MASS.) 2019; 20:S2-S12. [PMID: 31152178 PMCID: PMC6544553 DOI: 10.1093/pm/pnz075] [Citation(s) in RCA: 224] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The objective of this review was to merge current treatment guidelines and best practice recommendations for management of neuropathic pain into a comprehensive algorithm for primary physicians. The algorithm covers assessment, multidisciplinary conservative care, nonopioid pharmacological management, interventional therapies, neurostimulation, low-dose opioid treatment, and targeted drug delivery therapy. METHODS Available literature was identified through a search of the US National Library of Medicine's Medline database, PubMed.gov. References from identified published articles also were reviewed for relevant citations. RESULTS The algorithm provides a comprehensive treatment pathway from assessment to the provision of first- through sixth-line therapies for primary care physicians. Clear indicators for progression of therapy from firstline to sixth-line are provided. Multidisciplinary conservative care and nonopioid medications (tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentanoids, topicals, and transdermal substances) are recommended as firstline therapy; combination therapy (firstline medications) and tramadol and tapentadol are recommended as secondline; serotonin-specific reuptake inhibitors/anticonvulsants/NMDA antagonists and interventional therapies as third-line; neurostimulation as a fourth-line treatment; low-dose opioids (no greater than 90 morphine equivalent units) are fifth-line; and finally, targeted drug delivery is the last-line therapy for patients with refractory pain. CONCLUSIONS The presented treatment algorithm provides clear-cut tools for the assessment and treatment of neuropathic pain based on international guidelines, published data, and best practice recommendations. It defines the benefits and limitations of the current treatments at our disposal. Additionally, it provides an easy-to-follow visual guide of the recommended steps in the algorithm for primary care and family practitioners to utilize.
Collapse
Affiliation(s)
| | - B Carsten Schultheis
- Muskuloskelettales Zentrum - Interventionelle Schmerztherapie, Krankenhaus Neuwerk “Maria von den Aposteln,” Mönchengladbach, Germany
| | | | - Suneil M Jolly
- Louisiana Pain Specialists, New Orleans, Louisiana
- New Orleans East Hospital, New Orleans, Louisiana
| | - Krishnan V Chakravarthy
- Department of Anesthesiology and Pain Medicine, University of California San Diego Health Sciences, La Jolla, California
- Veterans Administration San Diego Healthcare System, San Diego, California
| | - Timothy R Deer
- The Spine and Nerve Center of the Virginias, Charleston, West Virginia
| | | | - Corey W Hunter
- Ainsworth Institute of Pain Management, New York, New York, USA
| |
Collapse
|
|
25
|
Designing and conducting proof-of-concept chronic pain analgesic clinical trials. Pain Rep 2019; 4:e697. [PMID: 31583338 PMCID: PMC6749910 DOI: 10.1097/pr9.0000000000000697] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 09/24/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023] Open
Abstract
Introduction: The evolution of pain treatment is dependent on successful development and testing of interventions. Proof-of-concept (POC) studies bridge the gap between identification of a novel target and evaluation of the candidate intervention's efficacy within a pain model or the intended clinical pain population. Methods: This narrative review describes and evaluates clinical trial phases, specific POC pain trials, and approaches to patient profiling. Results: We describe common POC trial designs and their value and challenges, a mechanism-based approach, and statistical issues for consideration. Conclusion: Proof-of-concept trials provide initial evidence for target use in a specific population, the most appropriate dosing strategy, and duration of treatment. A significant goal in designing an informative and efficient POC study is to ensure that the study is safe and sufficiently sensitive to detect a preliminary efficacy signal (ie, a potentially valuable therapy). Proof-of-concept studies help avoid resources wasted on targets/molecules that are not likely to succeed. As such, the design of a successful POC trial requires careful consideration of the research objective, patient population, the particular intervention, and outcome(s) of interest. These trials provide the basis for future, larger-scale studies confirming efficacy, tolerability, side effects, and other associated risks.
Collapse
|
|
26
|
|
|
27
|
Busse JW, Wang L, Kamaleldin M, Craigie S, Riva JJ, Montoya L, Mulla SM, Lopes LC, Vogel N, Chen E, Kirmayr K, De Oliveira K, Olivieri L, Kaushal A, Chaparro LE, Oyberman I, Agarwal A, Couban R, Tsoi L, Lam T, Vandvik PO, Hsu S, Bala MM, Schandelmaier S, Scheidecker A, Ebrahim S, Ashoorion V, Rehman Y, Hong PJ, Ross S, Johnston BC, Kunz R, Sun X, Buckley N, Sessler DI, Guyatt GH. Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis. JAMA 2018; 320:2448-2460. [PMID: 30561481 PMCID: PMC6583638 DOI: 10.1001/jama.2018.18472] [Citation(s) in RCA: 484] [Impact Index Per Article: 69.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
IMPORTANCE Harms and benefits of opioids for chronic noncancer pain remain unclear. OBJECTIVE To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain. DATA SOURCES AND STUDY SELECTION The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control. DATA EXTRACTION AND SYNTHESIS Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence. MAIN OUTCOMES AND MEASURES The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting. RESULTS Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], -0.69 cm [95% CI, -0.82 to -0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low- to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, -0.60 cm [95% CI, -1.54 to 0.34 cm]; physical functioning: WMD, -0.90 points [95% CI, -2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, -0.13 cm [95% CI, -0.99 to 0.74 cm]; physical functioning: WMD, -5.31 points [95% CI, -13.77 to 3.14 points]), and anticonvulsants (pain: WMD, -0.90 cm [95% CI, -1.65 to -0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, -5.77 to 6.66 points]). CONCLUSIONS AND RELEVANCE In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.
Collapse
Affiliation(s)
- Jason W. Busse
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, Ontario, Canada
| | - Li Wang
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
- Chinese Cochrane Centre, West China Hospital, Sichuan University, Chengdu
| | | | - Samantha Craigie
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - John J. Riva
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Luis Montoya
- Krembil Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Sohail M. Mulla
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Now with the Canadian Agency for Drugs and Technologies in Health (CADTH), Toronto, Ontario, Canada
| | - Luciane C. Lopes
- Pharmaceutical Science, University of Sorocaba, Sao Paulo, Brazil
| | - Nicole Vogel
- Leonardo Hirslanden Klinik Birshof, Münchenstein, Switzerland
| | - Eric Chen
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Karin Kirmayr
- Department of Internal Medicine, Hospital Alemán de Buenos Aires, Buenos Aires, Argentina
| | - Kyle De Oliveira
- Department of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Lori Olivieri
- Department of Anesthesiology, Perioperative and Pain Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Alka Kaushal
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Family Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
| | - Luis E. Chaparro
- Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
| | - Inna Oyberman
- Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
| | - Arnav Agarwal
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Rachel Couban
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
| | - Ludwig Tsoi
- Accident and Emergency Department, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Tommy Lam
- Accident and Emergency Department, Tuen Mun Hospital, Hong Kong, China
| | - Per Olav Vandvik
- Department of Medicine, Gjøvik, Innlandet Hospital Trust, Norway
| | - Sandy Hsu
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Malgorzata M. Bala
- Department of Hygiene and Dietetics, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Stefan Schandelmaier
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Institute for Clinical Epidemiology and Biostatistics, University of Basel Hospital, Basel, Switzerland
- Department of Clinical Research, University of Basel Hospital, Basel, Switzerland
| | - Anne Scheidecker
- Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
- Department of Anesthesiology, Operative Intensive Care, Preclinical Emergency Medicine and Pain Management, University of Basel Hospital, Basel, Switzerland
| | - Shanil Ebrahim
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Vahid Ashoorion
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Isfahan Medical Education Research Centre, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Yasir Rehman
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Canadian Academy of Osteopathy, Hamilton, Ontario, Canada
| | - Patrick J. Hong
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Stephanie Ross
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Bradley C. Johnston
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Regina Kunz
- Department of Clinical Research, University of Basel Hospital, Basel, Switzerland
| | - Xin Sun
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Chinese Cochrane Centre, West China Hospital, Sichuan University, Chengdu
| | - Norman Buckley
- Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
- Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
| | - Daniel I. Sessler
- Department of Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio
| | - Gordon H. Guyatt
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| |
Collapse
|
|
28
|
Martínez-Navarro M, Maldonado R, Baños JE. Why mu-opioid agonists have less analgesic efficacy in neuropathic pain? Eur J Pain 2018; 23:435-454. [PMID: 30318675 DOI: 10.1002/ejp.1328] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 09/06/2018] [Accepted: 10/10/2018] [Indexed: 12/29/2022]
Abstract
Injury to peripheral nerves often leads to abnormal pain states (hyperalgesia, allodynia and spontaneous pain), which can remain long after the injury heals. Although opioid agonists remain the gold standard for the treatment of moderate to severe pain, they show reduced efficacy against neuropathic pain. In addition to analgesia, opioid use is also associated with hyperalgesia and analgesia tolerance, whose underlying mechanisms share some commonalities with nerve injury-induced hypersensitivity. Here, we reviewed up-to-day research exploring the contribution of mu-opioid receptor (MOR) on the pathophysiology of neuropathic pain and on analgesic opioid actions under these conditions. We focused on the specific contributions of MOR populations at peripheral, spinal and supraspinal level. Moreover, evidences of neuroplastic changes that may underlie the low efficacy of MOR agonists under neuropathic pain conditions are reviewed and discussed. Sensitization processes leading to pain hypersensitivity, molecular changes in signalling pathways triggered by MOR and glial activation are some of these mechanisms elicited by both nerve injury and opioid exposure. Nerve injury-induced pain hypersensitivity might be masking the initial analgesic effects of opioid agonists, and alternatively, sustained opioid treatment to individuals already suffering from neuropathic pain could aggravate their pathophysiological state. Finally, some combined therapies that can increase opioid analgesic effectiveness in neuropathic pain treatment are highlighted. SIGNIFICANCE: This review provides evidence of the low benefit of opioid monotherapy in neuropathic pain and analyses the reasons of this reduced effectiveness. Opioid agonists along with drugs targeted to block the sensitization processes induced by MOR stimulation might result in a better management of neuropathic pain.
Collapse
Affiliation(s)
- Miriam Martínez-Navarro
- Department of Experimental and Health Sciences, Laboratory of Neuropharmacology, Universitat Pompeu Fabra, Barcelona, Spain
| | - Rafael Maldonado
- Department of Experimental and Health Sciences, Laboratory of Neuropharmacology, Universitat Pompeu Fabra, Barcelona, Spain
| | - Josep-E Baños
- Department of Experimental and Health Sciences, Laboratory of Neuropharmacology, Universitat Pompeu Fabra, Barcelona, Spain
| |
Collapse
|
|
29
|
Abstract
Central neuropathic pain can be difficult to treat and, subsequently, cause a great amount of disability and distress to patients, which limits quality of life. Common etiologies include the following: stroke, spinal cord injury, multiple sclerosis, infection, vasculitis, and malignancy. This case is a description of an 18-yr-old male patient diagnosed with a grade IV diffuse glioma who experienced severe neuropathic pain refractory to first-line treatment options including the following: gabapentinoids, tricyclic antidepressants, and selective serotonin and norepinephrine reuptake inhibitors. The patient remained on high-dose oral gabapentin as well as methadone and high-dose oxycodone for pain control at the time of submission. The aims of this case report were to review the nociceptive pathways and to explore the role of opioids in central neuropathic pain secondary to neoplasm because a better understanding of these topics can aid physiatrists in better taking care of these patients and improving function and quality of life.
Collapse
|
|
30
|
Norouzi MR, Ghasemi-Mobarakeh L, Gharibi H, Meamar R, Ajalloueian F, Chronakis IS. Surface modification of poly (ethylene terephthalate) fabric by soy protein isolate hydrogel for wound dressing application. INT J POLYM MATER PO 2018. [DOI: 10.1080/00914037.2018.1493684] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
| | | | - Hamidreza Gharibi
- Department of Chemistry, Isfahan University of Technology, Isfahan, Iran
| | - Rokhsareh Meamar
- Isfahan Clinical Toxicology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Ajalloueian
- Research Group for Nano-Bio Science, National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Ioannis S. Chronakis
- Research Group for Nano-Bio Science, National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| |
Collapse
|
|
31
|
Abstract
Patients experiencing a terminal drug related event reflect a sentinel event. If this pharmacotherapy is a widely used agent, it may be viewed as a catastrophic problem. If patients are dying from illegal drug use when the medical establishment fails them by withdrawing or minimizing their medically prescribed medication, then the burden rests with their health care providers, legislation, and insurance carriers to actively participate in a collegial fashion to achieve parity. Causing a decay in functionality in previously functional patients, may occur with appropriately prescribed opioid medications addressing non-cancer pain when withdrawing or diminishing either with or without patient consent. The members of the medical profession have diminished their prescribing of opioids for their patients out of apparent fear of reprisal, state or federal government sanctions, and other concerned groups. Diminishing former dosages or deleting the opioid medication, preferably in concert with the patient, often results in inequitable patient care. Enforcing sanctioned decreases or ceasing to prescribe from their former required/established opioid medications precipitate patient discord. In absence of opioid misuse, abuse, diversion or addiction based upon medical "guidelines" and with a poor foundation of Evidence Based Medicine the CDC guidelines, it may be masked as a true guideline reflecting a decrement of clinical judgment, wisdom, and compassion. This article also discusses the role of pharmacy chains, insurance carriers, and their pharmacy benefit managers (PBMs) contribution to this multidimensional problem. There may be a potential solution, identified in this paper, if all the associated political, medical and insurance groups work cohesively to improve patient care. This article and the CDC guidelines are not focused at hospice, palliative, end of life care pain management.
Collapse
Affiliation(s)
- Gary W Jay
- Clinical Professor, Department of Neurology, University of North Carolina, United States
| | - Robert L Barkin
- Professor, Rush University Medical College, Departments of Anesthesiology, Family Medicine, Pharmacology, Clinical Pharmacologist Department of Anesthesiology, Pain Centers of Skokie and Evanston Hospitals, NorthShore University Health System, IL, United States.
| |
Collapse
|
|
32
|
Abstract
PURPOSE OF REVIEW Neuropathic pain is a frequently encountered condition that is often resistant to treatment and is associated with poor patient satisfaction of their treatment. Several medications have been shown to be effective in treating neuropathic pain associated with diabetic neuropathy and postherpetic neuralgia, and these medications are often used to treat neuropathic pain associated with other conditions as well. This article summarizes the diagnosis and assessment of patients with neuropathic pain as well as available pharmacologic and interventional treatment options. RECENT FINDINGS Evidence-based recommendations for the treatment of neuropathic pain have been published, and first-line medications include antidepressants, anticonvulsants, topical agents, as well as opioid analgesics. Interventional options include anesthetic and steroid injections, nerve blocks, and spinal cord stimulation. Essential to the treatment algorithm of neuropathic pain is the assessment and treatment of psychosocial comorbidities and the utilization of a multidisciplinary team approach, including cognitive-behavioral and rehabilitative therapies. Questions remain about the comparative effectiveness of various medications and combination therapies. Increasing interest also exists in the optimization and personalization of pharmacotherapy based upon the underlying mechanism(s) of neuropathic pain according to the quality of the patient's symptoms. SUMMARY The management of chronic neuropathic pain is challenging and is best achieved with the use of a multidisciplinary team. Pain is a subjective experience, and it is important to validate a patient's pain, address psychosocial comorbidities, and set realistic treatment goals. Evidence-based guidelines are available to guide treatment, but frequently, high-quality evidence-based recommendations are lacking.
Collapse
|
|
33
|
Pergolizzi JV, Taylor R, LeQuang JA, Raffa RB, Bisney J. Tapentadol Extended Release in the Treatment of Severe Chronic Low Back Pain and Osteoarthritis Pain. Pain Ther 2018; 7:37-57. [PMID: 29623654 PMCID: PMC5993688 DOI: 10.1007/s40122-018-0095-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Indexed: 12/28/2022] Open
Abstract
Tapentadol is a novel pain reliever with apparently synergistic dual mechanisms of action, capable of addressing both nociceptive and neuropathic components of chronic pain. As an effective analgesic with good tolerability, tapentadol may be appropriate for patients suffering from severe chronic pain associated with low back pain (LBP) or osteoarthritis (OA). Efficacy studies of tapentadol in populations of patients with severe chronic LBP or OA pain suggest that tapentadol is non-inferior to oxycodone. Its tolerability, especially with respect to gastrointestinal (GI) side effects, may be better than that of other strong opioids in clinical trials and analyses of multiple trials. Patient satisfaction with tapentadol extended release for chronic noncancer pain syndromes is good. Although tapentadol has an opioid component with abuse liability, it appears to be a difficult opioid for tampering with less appeal to abusers than other opioids. For patients with severe LBP and OA pain, tapentadol appears to hold promise as a safe, effective therapeutic option.
Collapse
Affiliation(s)
| | | | | | - Robert B Raffa
- University of Arizona College of Pharmacy, Tucson, AZ, USA.,Temple University School of Pharmacy, Philadelphia, PA, USA
| | | |
Collapse
|
|
34
|
Pregabalin and Gabapentin for Post-Photorefractive Keratectomy Pain: A Randomized Controlled Trial. Eur J Ophthalmol 2018; 22 Suppl 7:S106-13. [DOI: 10.5301/ejo.5000143] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2012] [Indexed: 11/20/2022]
|
|
35
|
|
|
36
|
Kane CM, Mulvey MR, Wright S, Craigs C, Wright JM, Bennett MI. Opioids combined with antidepressants or antiepileptic drugs for cancer pain: Systematic review and meta-analysis. Palliat Med 2018; 32:276-286. [PMID: 28604172 DOI: 10.1177/0269216317711826] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Combining antidepressant or antiepileptic drugs with opioids has resulted in increased pain relief when used for neuropathic pain in non-cancer conditions. However, evidence to support their effectiveness in cancer pain is lacking. AIM To determine if there is additional benefit when opioids are combined with antidepressant or antiepileptic drugs for cancer pain. DESIGN Systematic review and meta-analysis. Randomised control trials comparing opioid analgesia in combination with antidepressant or antiepileptic drugs versus opioid monotherapy were sought. Data on pain and adverse events were extracted. Data were pooled using DerSimonian-Laird random-effects meta-analyses, and heterogeneity was assessed. RESULTS Seven randomised controlled trials that randomised 605 patients were included in the review. Patients' pain was described as neuropathic cancer pain, cancer bone pain and non-specific cancer pain. Four randomised controlled trials were included in the meta-analysis in which opioid in combination with either gabapentin or pregabalin was compared with opioid monotherapy. The pooled standardised mean difference was 0.16 (95% confidence interval, -0.19, 0.51) showing no significant difference in pain relief between the groups. Adverse events were more frequent in the combination arms. Data on amitriptyline, fluvoxamine and phenytoin were inconclusive. CONCLUSION Combining opioid analgesia with gabapentinoids did not significantly improve pain relief in patients with tumour-related cancer pain compared with opioid monotherapy. Due to the heterogeneity of patient samples, benefit in patients with definite neuropathic cancer pain cannot be excluded. Clinicians should balance the small likelihood of benefit in patients with tumour-related cancer pain against the increased risk of adverse effects of combination therapy.
Collapse
Affiliation(s)
- Chris M Kane
- 1 Academic Unit of Palliative Care, Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Matthew R Mulvey
- 1 Academic Unit of Palliative Care, Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Sophie Wright
- 1 Academic Unit of Palliative Care, Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Cheryl Craigs
- 1 Academic Unit of Palliative Care, Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Judy M Wright
- 2 Academic Unit of Health Economics, Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| | - Michael I Bennett
- 1 Academic Unit of Palliative Care, Leeds Institute of Health Sciences, School of Medicine, University of Leeds, Leeds, UK
| |
Collapse
|
|
37
|
|
|
38
|
Kim BS, Jin JY, Kwon JH, Woo IS, Ko YH, Park SY, Park HJ, Kang JH. Efficacy and safety of oxycodone/naloxone as add-on therapy to gabapentin or pregabalin for the management of chemotherapy-induced peripheral neuropathy in Korea. Asia Pac J Clin Oncol 2017; 14:e448-e454. [PMID: 29280313 DOI: 10.1111/ajco.12822] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 09/28/2017] [Indexed: 12/12/2022]
Abstract
AIMS To investigate the efficacy and safety of oxycodone/naloxone in patients with chemotherapy-induced peripheral neuropathy (CIPN) inadequately controlled with pregabalin or gabapentin. METHODS This 4-week, multicenter, interventional, single-arm phase IV study included 72 Korean patients with CIPN inadequately controlled with pregabalin or gabapentin (Numeric Rating Scale 0-10; NRS ≥4 at baseline). In addition to pregabalin or gabapentin at existing doses, patients received 20/10 mg/day oxycodone/naloxone (up-titrated to 80/40 mg/day as needed). The primary endpoint was change in NRS score after 4 weeks. Secondary endpoints included Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) scores and safety assessments. RESULTS The mean ± standard deviation (SD) dose of oxycodone/naloxone was 23.3 ± 7.5 mg/day. At week 4, NRS score reduction was 1.29 ± 1.84 points (21.4% reduction; P < 0.0001). Patients on taxane-based chemotherapy experienced a significantly smaller mean change in NRS score at week 4 compared to patients on other chemotherapy (-0.63 ± 1.54 [n = 30] vs. -1.83 ± 1.00 [n = 36]; P = 0.0072). Although there were no significant changes in FACT/GOG-NTX total scores, improvements were observed in the neurotoxicity subscale measuring numbness/tingling of hands (mean ± SD change: -0.27 ± 1.04; P = 0.0427) and feet (-0.60 ± 1.09; P < 0.0001). Forty-two (58.3%) patients reported adverse events. There were no clinically significant changes in laboratory tests or vital signs. CONCLUSION Oxycodone/naloxone added to pregabalin or gabapentin provided additional pain relief and symptom control in Korean patients with CIPN, without clinically significant safety concerns.
Collapse
Affiliation(s)
- Bong-Seog Kim
- Division of Hemato-Oncology, VHS Medical Center, Seoul, South Korea
| | - Jong-Youl Jin
- Division of Hemato-Oncology, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon, South Korea
| | - Jung Hye Kwon
- Division of Hemato-Oncology, Kangdong Sacred Heart Hospital, Hallym University, Seoul, South Korea
| | - In Sook Woo
- Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yoon Ho Ko
- Division of Oncology, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbu, South Korea
| | - Suk-Young Park
- Division of Oncology, Daejeon St. Mary's Hospital, The Catholic University of Korea, Daejeon, South Korea
| | - Hye-Jeong Park
- Medical Affairs, Mundipharma Korea Ltd., Seoul, South Korea
| | - Jin Hyung Kang
- Division of Medical Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| |
Collapse
|
|
39
|
Abstract
Introduction Phantom limb pain (PLP) is a complex condition resulting in pain in the missing limb affecting 60-80% amputees. Increasing number of patients are undergoing amputations. Approximately 1 per every 1000 people in the United Kingdom is an amputee. Incidence of PLP can be as high as 80% following amputation. PLP can be severe and difficult to treat. A range of pharmacological interventions exist yet little is known about them in respect to PLP. This article will address the effectiveness of both single pharmacological, therapy as well as drug combination therapy. Methods We reviewed all literature looking at the evidence for the efficacy of both single and combined pharmacological therapy in the management of phantom limb pain. Not all commonly prescribed analgesic agents have been studied in the use of PLP and in these cases, the evidence of their efficacy in neuropathic pain was reviewed. Conclusion It is difficult to draw definitive conclusions on the pharmacological management of PLP based on current available evidence. Most trials involved small cohorts and were not specific to the PLP. The trials which looked specifically at the PLP population gave conflicting results. Only the N-methyl-d-aspartate (NMDA) receptor antagonist class demonstrated consistent positive results. Most notably ketamine did produce a reduction in pressure pain thresholds and pain windup associated with PLP, although the numbers in these studies remain small. This benefit was not demonstrated across all NMDA receptor antagonists. Combination therapy has demonstrated effectiveness in previous studies for neuropathic pain but this has never been tested specifically against a PLP cohort. Therefore, combination treatment of agents with proven efficacy in PLP such as opioid and gabapentin deserves a closer examination in a controlled study against a placebo as well as single drug therapy.
Collapse
Affiliation(s)
- Neil Hall
- The James Cook University Hospital, Middlesbrough, UK
| | - Sam Eldabe
- The James Cook University Hospital, Middlesbrough, UK
| |
Collapse
|
|
40
|
Crowe MS, Wilson CD, Leishman E, Prather PL, Bradshaw HB, Banks ML, Kinsey SG. The monoacylglycerol lipase inhibitor KML29 with gabapentin synergistically produces analgesia in mice. Br J Pharmacol 2017; 174:4523-4539. [PMID: 28963716 DOI: 10.1111/bph.14055] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 08/25/2017] [Accepted: 09/14/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND PURPOSE Gabapentin is commonly prescribed for nerve pain but may also cause dizziness, sedation and gait disturbances. Similarly, inhibition of the endogenous cannabinoid enzyme monoacylglycerol lipase (MAGL) has antinociceptive and anti-inflammatory properties but also induces sedation in mice at high doses. To limit these side effects, the present study investigated the analgesic effects of coadministering a MAGL inhibitor with gabapentin. EXPERIMENTAL APPROACH Mice subjected to the chronic constriction injury model of neuropathic pain were administered the MAGL inhibitor KML29 (1-40 mg·kg-1 , i.p.), gabapentin (1-50 mg·kg-1 , i.p.) or both compounds. Mice were tested for mechanical and cold allodynia. The function and expression of cannabinoid CB1 receptors in whole brain homogenates and lipid profile of spinal cords were assessed after repeated drug administration. KEY RESULTS The combination of low-dose KML29:gabapentin additively attenuated mechanical allodynia and synergistically reduced cold allodynia. The CB1 antagonist, rimonabant, partially reversed the anti-allodynic effects of KML29:gabapentin in mechanical allodynia but not cold allodynia. The anti-allodynic effects of KML29:gabapentin did not undergo tolerance in mechanical allodynia after repeated administration but produced mild tolerance in cold allodynia. High dose KML29 alone reduced CB1 receptor expression and function, but KML29:gabapentin reduced the density of CB1 receptors but did not alter their function. KML29:gabapentin influenced additional signalling pathways (including fatty acids) other than the pathways activated by a higher dose of either drug alone. CONCLUSION AND IMPLICATIONS These data support the strategy of combining MAGL inhibition with a commonly prescribed analgesic as a therapeutic approach for attenuating neuropathic pain.
Collapse
Affiliation(s)
- Molly S Crowe
- Department of Psychology, West Virginia University, Morgantown, WV, USA.,Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA
| | - Catheryn D Wilson
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Emma Leishman
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - Paul L Prather
- Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Heather B Bradshaw
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - Matthew L Banks
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - Steven G Kinsey
- Department of Psychology, West Virginia University, Morgantown, WV, USA
| |
Collapse
|
|
41
|
Pineda-Farias JB, Caram-Salas NL, Salinas-Abarca AB, Ocampo J, Granados-Soto V. Ultra-Low Doses of Naltrexone Enhance the Antiallodynic Effect of Pregabalin or Gabapentin in Neuropathic Rats. Drug Dev Res 2017; 78:371-380. [PMID: 28868795 DOI: 10.1002/ddr.21409] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/14/2017] [Indexed: 11/06/2022]
Abstract
Preclinical Research Treatment of neuropathic pain is an area of largely unmet medical need. Pregabalin and gabapentin are anticonvulsants widely used for the treatment of neuropathic pain. Unfortunately, these drugs are only effective in 50-60% of the treated patients. In addition, both drugs have substantial side effects. Several studies have reported that ultralow doses of opioid receptor antagonists can induce analgesia and enhance the analgesic effect of opioids in rodents and humans. The objective of the present study was to assess the antiallodynic synergistic interaction between gabapentinoids and naltrexone in rats. Oral administration of pregabalin (ED50 = 2.79 ± 0.16 mg/kg) or gabapentin (ED50 = 21.04 ± 2.87 mg/kg) as well as intrathecal naltrexone (ED50 = 0.11 ± 0.02 ng) reduced in a dose-dependent manner tactile allodynia in rats. Maximal antiallodynic effects (∼100%) were reached with 30 mg/kg of pregabalin, 300 mg/kg of gabapentin or 0.5 ng of naltrexone. Co-administration of pregabalin or gabapentin and naltrexone in a fixed-dose ratio (1:1) remarkably reduced spinal nerve ligation-induced tactile allodynia showing a synergistic interaction. The data indicate that combinations of pregabalin or gabapentin and ultra-low doses of naltrexone are able to reduce tactile allodynia in neuropathic rats with lower doses that those used when drugs are given individually and with an improved side effects profile. Drug Dev Res 78 : 371-380, 2017. © 2017 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Jorge B Pineda-Farias
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Unidad Coapa Calzada de los Tenorios 235, Col. Granjas Coapa, Tlalpan, 14330, Ciudad de México, Mexico
| | - Nadia L Caram-Salas
- Catedra Conacyt, Estudios Moleculares Avanzados, Instituto de Ecología AC (INECOL). Carretera antigua a Coatepec 351, El Haya, Xalapa, Veracruz, Mexico
| | - Ana B Salinas-Abarca
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Unidad Coapa Calzada de los Tenorios 235, Col. Granjas Coapa, Tlalpan, 14330, Ciudad de México, Mexico
| | - Jorge Ocampo
- Laboratorio Médico Químico Biológico S.A. de C.V. (Bioquimed), Ciudad de México, Mexico
| | - Vinicio Granados-Soto
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Unidad Coapa Calzada de los Tenorios 235, Col. Granjas Coapa, Tlalpan, 14330, Ciudad de México, Mexico
| |
Collapse
|
|
42
|
Jung YH, Kim YO, Han JH, Kim YC, Yoon MH. Isobolographic Analysis of Drug Combinations With Intrathecal BRL52537 (κ-Opioid Agonist), Pregabalin (Calcium Channel Modulator), AF 353 (P2X3 Receptor Antagonist), and A804598 (P2X7 Receptor Antagonist) in Neuropathic Rats. Anesth Analg 2017; 125:670-677. [PMID: 28277328 DOI: 10.1213/ane.0000000000001883] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND Neuropathic pain should be treated with drug combinations exhibiting multiple analgesic mechanisms of action because the mechanism of neuropathic pain involves multiple physiological causes and is mediated by multiple pathways. In this study, we defined the pharmacological interaction of BRL52537 (κ-opioid agonist), pregabalin (calcium channel modulator), AF 353 (P2X3 receptor antagonist), and A804598 (P2X7 receptor antagonist). METHODS Animal models of neuropathic pain were established by spinal nerve ligation (SNL) in male Sprague-Dawley rats, and responses to the mechanical stimulation using von Frey filaments were measured. Drugs were administered by intrathecal route and were examined for antiallodynic effects, and drug interactions were evaluated using isobolographic analysis. The mRNA expression levels of pain-related receptors in each spinal cord or dorsal root ganglion of naïve, SNL, and drug-treated SNL rats were evaluated using real-time polymerase chain reaction. RESULTS Intrathecal BRL52537, pregabalin, AF 353, and A804598 produced antiallodynic effects in SNL rats. In the drug combination studies, intrathecal coadministration of BRL52537 with pregabalin or A804598 exhibited synergistic interactions, and other drugs combinations showed additivity. The rank order of potency was observed as follows: BRL52537 + pregabalin > BRL52537 + A804598 > pregabalin + AF 353 > A804598 + pregabalin > BRL52537 + AF 353 > AF 353 + A804598. Real-time polymerase chain reaction indicated that alterations of P2X3 receptor and calcium channel mRNA expression levels were observed, while P2X7 receptor and κ-opioid receptor expression levels were not altered. CONCLUSIONS These results demonstrated that intrathecal combination of BRL52537, pregabalin, AF 353, and A804598 synergistically or additively attenuated allodynia evoked by SNL, which suggests the possibility to improve the efficacy of single-drug administration.
Collapse
Affiliation(s)
- Young-Hwan Jung
- From the *School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea; †Department of Anesthesiology and Pain Medicine, Chonnam National University, Medical School, Gwangju, Republic of Korea; ‡Department of Biomedical Science and Engineering at Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea; and §Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Republic of Korea
| | | | | | | | | |
Collapse
|
|
43
|
Wattiez AS, Dupuis A, Privat AM, Chalus M, Chapuy E, Aissouni Y, Eschalier A, Courteix C. Disruption of 5-HT 2A-PDZ protein interaction differently affects the analgesic efficacy of SSRI, SNRI and TCA in the treatment of traumatic neuropathic pain in rats. Neuropharmacology 2017; 125:308-318. [PMID: 28780039 DOI: 10.1016/j.neuropharm.2017.07.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 07/27/2017] [Accepted: 07/31/2017] [Indexed: 01/17/2023]
Abstract
Antidepressants remain one of the first line treatments prescribed to neuropathic pain patients despite their limited efficacy and/or their numerous side effects. More and more, pharmacotherapy for neuropathic pain has evolved towards the use of therapeutic combinations. The goal of the present study was to assess the efficacy of the combination of antidepressants - selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors-with a peptide (TAT-2ASCV) able to disrupt the interaction between serotonin type 2A (5-HT2A) receptors and associated PDZ proteins. Mechanical hypersensitivity was assessed in sciatic nerve ligation-induced neuropathic pain in rats using paw pressure test after acute treatment with TAT-2ASCV alone or in combination with repeated treatment with fluoxetine or duloxetine or clomipramine. First, we validated the anti-hyperalgesic effect of TAT-2ASCV on mechanical hypersensitivity at the dose of 100 ng/rat (single i.t. injection). Second, using selective receptor antagonists, we found that the effect of TAT-2ASCV on mechanical hypersensitivity involves 5-HT2A as well as GABAA receptors. Finally, we showed that the association of TAT-2ASCV (100 ng, single i.t. injection) with fluoxetine (10 mg/kg, five i.p. injections) reveals its anti-hyperalgesic effect, while the association with duloxetine (1 mg/kg, five i.p. injections) or clomipramine (2.5 mg/kg, five i.p. injections) is only additive. Those results further accentuate the interest to develop small molecules acting like TAT-2ASCV in order to treat neuropathic pain as a monotherapy or in combination with antidepressants.
Collapse
Affiliation(s)
- Anne-Sophie Wattiez
- Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France
| | - Amandine Dupuis
- Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France
| | - Anne-Marie Privat
- Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France
| | - Maryse Chalus
- Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France
| | - Eric Chapuy
- Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France
| | - Youssef Aissouni
- Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France
| | - Alain Eschalier
- Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France
| | - Christine Courteix
- Université Clermont Auvergne, INSERM U1107, NEURO-DOL, F-63000 Clermont-Ferrand, France.
| |
Collapse
|
|
44
|
Holbech JV, Jung A, Jonsson T, Wanning M, Bredahl C, Bach FW. Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process. J Pain Res 2017; 10:1467-1475. [PMID: 28721089 PMCID: PMC5499948 DOI: 10.2147/jpr.s138099] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Current Danish treatment algorithms for pharmacological treatment of neuropathic pain (NeP) are tricyclic antidepressants (TCA), gabapentin and pregabalin as first-line treatment for the most common NeP conditions. Many patients have insufficient pain relief on monotherapy, but combination therapy had not been included in guidelines until recently. Based on clinical empiricism and scientific evidence, a Delphi consensus process provided a consolidated guidance on pharmacological combination treatment of NeP. METHODS A two-round virtual internet-based Delphi process with 6 Danish pain specialists was undertaken. In the first round, questions were answered individually and anonymously, whereas in the second round, the panel openly discussed first round's summary of outcomes. Combinations of pharmacological pain treatments, that is, pregabalin/gabapentin, TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, opioids, other antiepileptics and cutaneous patches, were assessed based on both scientific and clinical practice experiences. The Centers for Disease Control and Prevention (CDC) grading system was used for evidence rating. RESULTS Combination of pregabalin/gabapentin with TCA is useful in patients who do not gain sufficient pain relief or tolerate either drug in high doses, or to improve sleep disturbance. Also, combination of pregabalin/gabapentin and SNRIs is reasonably well documented and experienced by some experts to result in sufficient pain relief and fewer side effects than monotherapy. Good evidence on efficacy was found for the combination of pregabalin/gabapentin or TCAs and opioids, which was also frequently used in clinical practice. The evidence for combining TCAs and SNRIs is insufficient, although sometimes used in clinical practice despite the risk of serotonin syndrome. For localized NeP, combination therapy with cutaneous patches should be considered. There was insufficient scientific evidence for any pharmacologic combination therapies with selective serotonin reuptake inhibitors - as well as for other potential combinations. CONCLUSIONS The study revealed that combination therapy is widely used in clinical practice and supported by some scientific evidence. However, further studies are needed.
Collapse
Affiliation(s)
| | - Anne Jung
- Medicinsk Fælles Ambulatorium, Holbaek Hospital
| | | | | | - Claus Bredahl
- Clinic Acute Orthopedic Surgical Anesthesia Section, Aalborg Universitetshospital, Aalborg
| | - Flemming W Bach
- Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
45
|
Buttram ME, Kurtz SP, Dart RC, Margolin ZR. Law enforcement-derived data on gabapentin diversion and misuse, 2002-2015: diversion rates and qualitative research findings. Pharmacoepidemiol Drug Saf 2017; 26:1083-1086. [PMID: 28493425 DOI: 10.1002/pds.4230] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 03/29/2017] [Accepted: 04/17/2017] [Indexed: 01/12/2023]
Abstract
PURPOSE Recent limited epidemiologic and case reports suggest that gabapentin is being misused, especially among prescription opioid misusers. However, no apparent studies have reported data from law enforcement on the diversion and misuse of gabapentin. METHODS Case report data are drawn from a quarterly survey of prescription drug diversion completed by a national sample of law enforcement and regulatory agencies who engage in drug diversion investigations. Rates of gabapentin diversion per 100 000 population were calculated for each quarter from 2002 through 2015. Qualitative data are drawn from a brief questionnaire completed by a subsample of survey respondents and were organized and presented by theme. RESULTS In total, 407 new cases of diverted gabapentin were reported during the time period, with diversion rates steadily increasing from zero cases in the first 2 quarters of 2002 to a high of 0.027 cases per 100 000 population in the fourth quarter of 2015. Qualitative data suggest that gabapentin is being misused in conjunction with prescription opioids and that gabapentin and heroin are being combined and consumed together. Law enforcement reporters found these drug use trends to be contributing to gabapentin diversion. CONCLUSIONS The recent increase in gabapentin diversion appears to be related to the opioid epidemic, based on law enforcement descriptions of gabapentin being misused in combination with opioids. Yet epidemiological data related to this finding is limited and research conducted among gabapentin misusers is needed to understand this problem in more depth. Greater monitoring of gabapentin abuse and diversion appear warranted.
Collapse
Affiliation(s)
- Mance E Buttram
- Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, Miami, FL, USA
| | - Steven P Kurtz
- Center for Applied Research on Substance Use and Health Disparities, Nova Southeastern University, Miami, FL, USA
| | | | | |
Collapse
|
|
46
|
Waldfogel JM, Nesbit SA, Dy SM, Sharma R, Zhang A, Wilson LM, Bennett WL, Yeh HC, Chelladurai Y, Feldman D, Robinson KA. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review. Neurology 2017; 88:1958-1967. [PMID: 28341643 DOI: 10.1212/wnl.0000000000003882] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 03/03/2017] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To systematically assess the effect of pharmacologic treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life. METHODS We searched PubMed and Cochrane Database of Systematic Reviews for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013, to May 24, 2016. We searched Clinicaltrials.gov on March 9, 2016. Two reviewers independently evaluated studies for eligibility, serially abstracted data, and independently evaluated risk of bias and graded strength of evidence (SOE). RESULTS We updated a recently completed systematic review of 57 eligible studies with 24 additional published studies and 25 unpublished studies. For reducing neuropathy-related pain, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine (moderate SOE), the anticonvulsants pregabalin and oxcarbazepine (low SOE), the drug classes tricyclic antidepressants (low SOE) and atypical opioids (low SOE), and botulinum toxin (low SOE) were more effective than placebo. We could not draw conclusions about quality of life due to incomplete reporting. All studies were short-term (less than 6 months), and all effective drugs had more than 9% dropouts from adverse effects. CONCLUSIONS For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo. However, quality of life was poorly reported, studies were short-term, drugs had substantial dropout rates, and opioids have significant risks. Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients' quality of life.
Collapse
Affiliation(s)
- Julie M Waldfogel
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA.
| | - Suzanne Amato Nesbit
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Sydney M Dy
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Ritu Sharma
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Allen Zhang
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Lisa M Wilson
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Wendy L Bennett
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Hsin-Chieh Yeh
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Yohalakshmi Chelladurai
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Dorianne Feldman
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| | - Karen A Robinson
- From the Department of Pharmacy (J.M.W., S.A.N.), The Johns Hopkins Hospital; Department of Health Policy & Management (S.M.D., R.S., A.Z., L.M.W.), Johns Hopkins Bloomberg School of Public Health; Division of General Internal Medicine (W.L.B., K.A.R.) and Department of Physical Medicine & Rehabilitation (D.F.), Johns Hopkins University School of Medicine; Departments of Medicine, Epidemiology, and Oncology (H.-C.Y.), Division of General Internal Medicine, Johns Hopkins University, Baltimore, MD; and Department of Internal Medicine (Y.C.), Morehouse School of Medicine, Atlanta, GA
| |
Collapse
|
|
47
|
Salimzade A, Hosseini-Sharifabad A, Rabbani M. Comparative effects of chronic administrations of gabapentin, pregabalin and baclofen on rat memory using object recognition test. Res Pharm Sci 2017. [PMID: 28626478 PMCID: PMC5465829 DOI: 10.4103/1735-5362.207201] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Memory impairment is one of the greatest concerns when it comes to long-term CNS-affecting drug administration. Drugs like gabapentin, pregabalin and baclofen are administered in a long-term period in conditions such as epilepsy, neuropathic pain, spasticity associated with spinal cord injury or multiple sclerosis. Despite their wide spread use, few data are available on the effects of these drugs on cognitive functions, such as learning memory. In the present study, the effects of long-term administration of gabapentin, pregabalin and baclofen on memory were investigated in a comparative manner. Male Wistar rats received intraperitoneal (i.p.) injection of gabapentin (30 mg/kg), pregabalin (30 mg/kg), baclofen (3 mg/kg), combination of gabapentin/baclofen (30/3 mg/kg) and combination of pregabalin/baclofen (30/3 mg/kg) once a day for 3 weeks respective to their groups. After the end of treatments, rat memories were assessed using the object-recognition task. The discrimination and recognition indices (RI and DI) in the T2 trials were used as the memory indicating factors. The results showed that daily i.p. administrations of pregabalin but not gabapentin or baclofen significantly decreased DI and RI compared to saline group. In combination groups, either gabapentin or pregabalin impaired discrimination between new and familiar objects. Our findings suggested that pregabalin alone or in combination with baclofen significantly caused cognitive deficits.
Collapse
Affiliation(s)
- Asma Salimzade
- Department of Pharmacology and Toxicology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Ali Hosseini-Sharifabad
- Department of Pharmacology and Toxicology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Mohammad Rabbani
- Department of Pharmacology and Toxicology and Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| |
Collapse
|
|
48
|
Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA, Sosenko JM, Ziegler D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care 2017; 40:136-154. [PMID: 27999003 PMCID: PMC6977405 DOI: 10.2337/dc16-2042] [Citation(s) in RCA: 1405] [Impact Index Per Article: 175.6] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Rodica Pop-Busui
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | | | - Eva L Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI
| | - Vera Bril
- Department of Neurology, University of Toronto, Toronto, Ontario, Canada
| | - Roy Freeman
- Department of Neurology, Harvard Medical School, Boston, MA
| | - Rayaz A Malik
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar and New York, NY
| | - Jay M Sosenko
- Division of Endocrinology, University of Miami Miller School of Medicine, Miami, FL
| | - Dan Ziegler
- German Diabetes Center Düsseldorf, Leibniz Center for Diabetes Research at Heinrich Heine University, and Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| |
Collapse
|
|
49
|
Deeks ED, Lyseng-Williamson KA. Oxycodone prolonged release: a guide to its use in the EU. DRUGS & THERAPY PERSPECTIVES 2016. [DOI: 10.1007/s40267-016-0326-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
|
|
50
|
Tsukanov J, Fabbro ED. Palliative care and symptom management in amyloidosis: A review. Curr Probl Cancer 2016; 40:220-228. [DOI: 10.1016/j.currproblcancer.2016.09.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 09/04/2016] [Accepted: 09/14/2016] [Indexed: 12/27/2022]
|