The importance of the type of pain medication in spinal disease is an ongoing matter of debate. Recent guidelines recommend acetaminophen and NSAIDs as first-line medication for lumbar disc herniation. However, opioid pain medication is commonly used in patients with chronic pain, and therefore also in patients with sciatica. The aim of this study is to evaluate if opioids have an impact on the outcome in patients suffering from lumbar disc herniation. To assess this objectively quantitative sensory testing (QST) was applied. In total, 52 patients with a single lumbar disc herniation confirmed on magnetic resonance imaging (MRI) and treated by lumbar sequesterectomy were included in the trial. Patients were analysed according to their preoperative opioid intake: 35 patients who did not receive opioids (group NO) and 17 patients, who received opioids preoperatively (group O). Further evaluation included detailed medical history, physical examination, various questionnaires, and QST. No pre- and postoperative differences were detected in thermal or mechanical thresholds (p > 0.05). Wind-up ratio (WUR) differed significantly between groups 1 week postoperatively (p = 0.025). The NRS for low back pain was rated significantly higher in the non-opioid group (NO) after 1-week follow-up (p = 0.026). Radicular pain tended to be higher in the NO group after 12 months of follow-up (p = 0.023). Opioids seem to be a positive predictor for the postoperative pain outcome in early follow-up in patients undergoing lumbar sequesterectomy. Furthermore, patients presented with less radicular pain 1 year after surgery.

• Lumbar disc herniation
• Lumbar radiculopathy
• Lumbar sequesterectomy
• Opioid therapy
• Quantitative sensory testing

The contact burn injury model is an experimental contact thermode-based physiological pain model primarily applied in research of drug efficacy in humans. The employment of the contact burn injury model across studies has been inconsistent regarding essential methodological variables, challenging the validity of the model. This systematic review analyzes methodologies, outcomes, and research applications of the contact burn injury model. Based on these results, we propose an improved contact burn injury testing paradigm. A literature search was conducted (15-JUL-2020) using PubMed, EMBASE, Web of Science, and Google Scholar. Sixty-four studies were included. The contact burn injury model induced consistent levels of primary and secondary hyperalgesia. However, the analyses revealed variations in the methodology of the contact burn injury heating paradigm and the post-burn application of test stimuli. The contact burn injury model had limited testing sensitivity in demonstrating analgesic efficacy. There was a weak correlation between experimental and clinical pain intensity variables. The data analysis was limited by the methodological heterogenicity of the different studies and a high risk of bias across the studies. In conclusion, although the contact burn injury model provides robust hyperalgesia, it has limited efficacy in testing analgesic drug response. Recommendations for future use of the model are being provided, but further research is needed to improve the sensitivity of the contact burn injury method. The protocol for this review has been published in PROSPERO (ID: CRD42019133734).

• Analgesics/therapeutic use
• Burns/drug therapy
• Burns/physiopathology
• Female
• Humans
• Hyperalgesia/drug therapy
• Hyperalgesia/physiopathology
• Male
• Models, Biological
• Pain/drug therapy
• Pain/physiopathology
• Pain Measurement

• R01 DA037621 NIDA NIH HHS
• National Institutes of Health

The cold pressor test (CPT) is widely implemented and offers a simple, experimental acute pain model utilizing cold pain. Previous trials have frequently paired the CPT with opioids in order to investigate the mechanisms underlying pharmacological analgesia, due to their known analgesic efficacy. However, opioid side effects may lead to unblinding and raise concerns about the safety of the experimental setting. Despite the established clinical efficacy of dipyrone (metamizole), its efficacy, tolerability, and safety in cold pressor pain has not been systematically addressed to date. This pooled analysis included data of 260 healthy volunteers from three randomized, placebo‐controlled, double‐blind substudies using the CPT following a pre‐test‐post‐test‐design. These substudies allow for comparing a single dose of 800 mg dipyrone with two different doses of the opioid tilidine/naloxone (50/4 mg and 100/8 mg, respectively). Outcomes included pain intensity ratings, pain tolerance, medication‐attributed side effects, as well as changes of blood pressure and heart rate. We demonstrate that both opioid doses and dipyrone had a comparable, significant analgesic effect on cold pressor pain. However, dipyrone was associated with significantly less self‐reported adverse effects and these were not significantly different from those under placebo. These results indicate that the combination of dipyrone and the CPT provides a safe, tolerable, and effective experimental model for the study of pharmacological analgesia. In combination with a CPT, dipyrone may be useful as a positive control, or baseline medication for the study of analgesic modulation.

As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock‐like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission.

We therefore performed a systematic literature review (PubMed‐Medline, Cochrane, WoS, ClinicalTrials) and semi‐quantitative meta‐analysis of human pain models that aim to induce central sensitization, and generate hyperalgesia surrounding a real or simulated injury.

From an initial set of 1569 reports, we identified and analysed 269 studies using more than a dozen human models of sensitization. Five of these models (intradermal or topical capsaicin, low‐ or high‐frequency electrical stimulation, thermode‐induced heat‐injury) were found to reliably induce secondary hyperalgesia to pinprick and have been implemented in multiple laboratories. The ability of these models to induce dynamic mechanical allodynia was however substantially lower. The proportion of subjects who developed hypersensitivity was rarely provided, giving rise to significant reporting bias. In four of these models pharmacological profiles allowed to verify similarity to some clinical conditions, and therefore may inform basic research for new drug development.

While there is no single “optimal” model of central sensitization, the range of validated and easy‐to‐use procedures in humans should be able to inform preclinical researchers on helpful potential biomarkers, thereby narrowing the translation gap between basic and clinical data.

Being able to mimic aspects of pathological pain directly in humans has a huge potential to understand pathophysiology and provide animal research with translatable biomarkers for drug development. One group of human surrogate models has proven to have excellent predictive validity: they respond to clinically active medications and do not respond to clinically inactive medications, including some that worked in animals but failed in the clinics. They should therefore inform basic research for new drug development.

The endogenous pain system may be used as a biomarker in the pharmacological treatment of patients with CLBP, enabling an individualized, mechanism-based treatment approach.

Chronic low back pain (CLBP) is one of the most common chronic pain conditions in pain practice.

In the current study, we describe phenotypes of patients with CLBP based on the status of their endogenous pain modulatory system.

Conditioned pain modulation (a measure of central pain inhibition), temporal summation (TS, a measure of pain facilitation), and offset analgesia (a measure of temporal filtering of nociception) were evaluated in 53 patients with CLBP at painful and nonpainful sites. Next, in a double-blind, randomized, placebo-controlled trial, 40 patients with defective conditioned pain modulation responses received treatment with tapentadol prolonged-release or placebo for 3 months.

The majority of patients (87%) demonstrated loss of central pain inhibition combined with segmentally increased TS and reduced offset analgesia at the lower back region. During treatment, tapentadol reduced pain intensity more than placebo (tapentadol −19.5 ± 2.1 mm versus placebo −7.1 ± 1.8 mm, P = 0.025). Furthermore, tapentadol significantly decreased pain facilitation by reduction of TS responses at the lower back (tapentadol −0.94 ± 1.9 versus placebo 0.01 ± 1.5, P = 0.020), which correlated with pain reduction (P < 0.001).

Patients with CLBP demonstrated different phenotypes of endogenous pain modulation. In patients with reduced conditioned pain modulation, tapentadol produced long-term pain relief that coincided with reduction of signs of pain facilitation. These data indicate that the endogenous pain system may be used as a biomarker in the pharmacological treatment of CLBP, enabling an individualized, mechanism-based treatment approach.

• Chronic low back pian
• Conditioned pain modulation
• Endogenous pain modulation
• Offset analgesia
• Temporal summation

• Ferula
• coumarins
• neuropathic pain
• oxidative stress
• sesquiterpene
• taxane

• Chronic pancreatitis
• analgesics
• chronic pain
• neurophysiology
• pain management
• pain measurements
• symptom assessment

Antidepressants are frequently prescribed as co-analgesics in chronic pain. While their efficacy is well documented for neuropathic pain, the evidence is less clear in musculoskeletal pain conditions. The present study therefore evaluated the effect of the tricyclic antidepressant imipramine on chronic low-back pain in a randomized, double-blinded placebo-controlled design. To explore the mechanisms of action and the influence of drug metabolism, multimodal quantitative sensory tests (QST) and genotyping for cytochrome P450 2D6 (CYP2D6) were additionally performed. A single oral dose of imipramine 75 mg was compared to active placebo (tolterodine 1 mg) in 50 patients (32 females) with chronic non-specific low-back pain. Intensity of low-back pain was assessed on a 0–10 numeric rating scale at baseline and every 30 minutes after drug intake. Multimodal QST were performed at baseline and in hourly intervals for 2 hours. Pharmacogenetic influences of cytochrome P450 were addressed by CYP2D6 genotyping. No significant analgesic effect was detected neither on low-back pain nor on any of the sensory tests in the overall analyses. However, evidence for an interaction of the imipramine effect and CYP2D6 genotype was found for electrical and for pressure pain detection thresholds. Intermediate but not extensive metabolizers had a 1.20 times greater electrical pain threshold (95%-CI 1.10 to 1.31) and a 1.10 times greater pressure pain threshold (95%-CI 1.01 to 1.21) 60 minutes after imipramine than after placebo (p<0.001 and p = 0.034, respectively). The present study failed to demonstrate an immediate analgesic effect of imipramine on low-back pain. Anti-nociceptive effects as assessed by quantitative sensory tests may depend on CYP2D6 genotype, indicating that metabolizer status should be accounted for when future studies with tricyclic antidepressants are undertaken.

• Adult
• Chronic Pain/drug therapy
• Chronic Pain/genetics
• Chronic Pain/metabolism
• Cytochrome P-450 CYP2D6/genetics
• Female
• Genotype
• Humans
• Imipramine/adverse effects
• Imipramine/therapeutic use
• Low Back Pain/drug therapy
• Low Back Pain/genetics
• Low Back Pain/metabolism
• Male
• Pain Measurement

• Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

This double-blind, crossover, randomized placebo-controlled study found that methylphenidate has a specific effect on nociceptive pathways rather than a generalized effect on aversive sensory modalities.

We recently showed that the psycho-stimulant norepinephrine–dopamine reuptake inhibitor methylphenidate (MP) prolonged cold pain threshold and tolerance in adults with attention-deficit hyperactivity disorder (ADHD).

The objectives of the present study were to: (1) examine whether MP has antinociceptive properties in healthy men; (2) test MP's effects on responses to aversive auditory stimuli. The underlying aim was to determine whether MP exerts antinociceptive properties or more generalized, nonspecific attenuating effects on different aversive sensory modalities.

This double-blind, crossover, randomized placebo-controlled study consisted of 2 sessions one week apart from each other. In each session, pain threshold (seconds) and tolerance (seconds) in response to painful cold stimulation were measured. Additionally, threshold (dB) and tolerance (seconds) to loud aversive auditory stimuli (500 Hz, 2000 Hz and white noise) were also tested prior to and 2 hours following the administration of a single dose of either 20 mg MP or an identical looking placebo.

Forty men, 26.1 ± 4.0 (mean ± SD) years were enrolled in the study. Wilcoxon signed-rank test analyses showed that MP, but not the placebo, produced a significant increase in cold pain threshold (from 4.1 ± 2.6 to 5.4 ± 3.1 seconds, P = 0.001 and from 4.5 ± 2.6 to 4.3 ± 2.7 seconds, P = 0.2, respectively) and tolerance (from 57.8 ± 54.0 to 73.8 ± 61.8 seconds, P = 0.001 and from 52.5 ± 53.7 sec to 57.0 ± 52.9 seconds, P = 0.1, respectively). No significant changes were found in any of the auditory parameters.

These results suggest that MP has an effect on nociceptive pathways rather than a nonspecific, generalized attenuating effect on aversive sensory stimuli.

• Dopamine
• Experimental pain
• Methylphenidate
• Norepinephrine
• Pain threshold
• Pain tolerance

• analgesics
• human pain models
• pharmacodynamics
• pharmacokinetics

• evoked pain
• intrathecal
• norepinephrine reuptake inhibitor
• pharmacodynamics
• pharmacokinetics

Inability to predict the therapeutic effect of a drug in individual pain patients prolongs the process of drug and dose finding until satisfactory pharmacotherapy can be achieved. Many chronic pain conditions are associated with hypersensitivity of the nervous system or impaired endogenous pain modulation. Pharmacotherapy often aims at influencing these disturbed nociceptive processes. Its effect might therefore depend on the extent to which they are altered. Quantitative sensory testing (QST) can evaluate various aspects of pain processing and might therefore be able to predict the analgesic efficacy of a given drug. In the present study three drugs commonly used in the pharmacological management of chronic low back pain are investigated. The primary objective is to examine the ability of QST to predict pain reduction. As a secondary objective, the analgesic effects of these drugs and their effect on QST are evaluated.

In this randomized, double blinded, placebo controlled cross-over study, patients with chronic low back pain are randomly assigned to imipramine, oxycodone or clobazam versus active placebo. QST is assessed at baseline, 1 and 2 h after drug administration. Pain intensity, side effects and patients’ global impression of change are assessed in intervals of 30 min up to two hours after drug intake. Baseline QST is used as explanatory variable to predict drug effect. The change in QST over time is analyzed to describe the pharmacodynamic effects of each drug on experimental pain modalities. Genetic polymorphisms are analyzed as co-variables.

Pharmacotherapy is a mainstay in chronic pain treatment. Antidepressants, anticonvulsants and opioids are frequently prescribed in a “trial and error” fashion, without knowledge however, which drug suits best which patient. The present study addresses the important need to translate recent advances in pain research to clinical practice. Assessing the predictive value of central hypersensitivity and endogenous pain modulation could allow for the implementation of a mechanism-based treatment strategy in individual patients.

Clinicaltrials.gov, NCT01179828

An experimental pain model which is sensitive and reproducible would be a useful pharmacological tool both for existing and new drugs. The aim of the present study was to establish a simple and reliable method of producing experimental pain which can be used for screening of analgesic agents.

The method was standardized by recording pain threshold and pain tolerance values in 24 healthy volunteers. Reproducibility of the test procedure was evaluated by recording the pain threshold and pain tolerance values by a single observer on two sessions (inter-day reproducibility), and second observer in one session (inter-observer reproducibility), separately. Validity of the model was further tested by evaluating the analgesic effect of tramadol in 12 healthy volunteers.

Cold pain model was found to produce low variability with coefficient of variation less than 15%. Inter-observer and inter-day reproducibility was very good as shown by Bland – Altman plot with most of the values within ± 2SD. Analgesic activity by Tramadol was statistically different from placebo (P < 0.05).

The newly developed pain model offers a stable and sensitive method for the early assessment of analgesic activity.

• Cold pain
• experimental
• pharmacodynamics
• tramadol

• Hyperalgesia
• catastrophizing
• conditioned pain modulation
• lumpectomy
• quantitative sensory testing
• temporal summation

• Aged
• Breast Neoplasms/physiopathology
• Breast Neoplasms/psychology
• Breast Neoplasms/surgery
• Catastrophization/physiopathology
• Catastrophization/psychology
• Cross-Sectional Studies
• Female
• Humans
• Mastectomy, Segmental/adverse effects
• Middle Aged
• Pain Measurement
• Pain Perception/physiology
• Pain Threshold/physiology
• Pain, Postoperative/physiopathology
• Pain, Postoperative/psychology

• K23 NS070933 NINDS NIH HHS
• R01 AG034982 NIA NIH HHS
• R21 CA120500 NCI NIH HHS

• Antidepressants
• HIV
• Neuropathic Pain
• Opioids

• Analgesics/administration & dosage
• Analgesics/pharmacology
• Analgesics/therapeutic use
• Animals
• Disease Models, Animal
• Humans
• Hyperalgesia/drug therapy
• Hyperalgesia/etiology
• Nontherapeutic Human Experimentation
• Pain Measurement
• Pain Threshold/drug effects
• Species Specificity

• Adult
• Anticonvulsants/adverse effects
• Anticonvulsants/pharmacology
• Anticonvulsants/therapeutic use
• Cross-Over Studies
• Double-Blind Method
• Electric Stimulation
• Female
• Humans
• Levetiracetam
• Male
• Neuralgia/drug therapy
• Neuralgia/etiology
• Pain Threshold/drug effects
• Piracetam/adverse effects
• Piracetam/analogs & derivatives
• Piracetam/pharmacology
• Piracetam/therapeutic use
• Reaction Time/drug effects
• Sural Nerve

• Adult
• Aged
• Analgesics/administration & dosage
• Analgesics/adverse effects
• Chronic Disease
• Cyclohexanols/administration & dosage
• Cyclohexanols/adverse effects
• Double-Blind Method
• Electric Stimulation/adverse effects
• Female
• Hot Temperature/adverse effects
• Humans
• Hyperalgesia/drug therapy
• Hyperalgesia/physiopathology
• Hyperalgesia/psychology
• Male
• Middle Aged
• Neuralgia/drug therapy
• Neuralgia/physiopathology
• Neuralgia/psychology
• Pain Measurement/drug effects
• Pain Threshold/drug effects
• Pain Threshold/physiology
• Pain, Intractable/drug therapy
• Pain, Intractable/physiopathology
• Pain, Intractable/psychology
• Peripheral Nervous System Diseases/drug therapy
• Peripheral Nervous System Diseases/physiopathology
• Peripheral Nervous System Diseases/psychology
• Physical Stimulation
• Placebos
• Time Factors
• Treatment Outcome
• Venlafaxine Hydrochloride

• Aged
• Benzothiazoles/therapeutic use
• Cold Temperature
• Cross-Sectional Studies
• Depression/physiopathology
• Dopamine Agonists/therapeutic use
• Female
• Hot Temperature
• Humans
• Male
• Middle Aged
• Pain Threshold/physiology
• Pramipexole
• Pressure
• Psychophysics
• Restless Legs Syndrome/drug therapy
• Restless Legs Syndrome/physiopathology
• Sleep Wake Disorders/physiopathology
• Surveys and Questionnaires

• R01 AR05487 NIAMS NIH HHS
• M01-RR002719 NCRR NIH HHS
• M01 RR002719 NCRR NIH HHS
• P01 AG021190 NIA NIH HHS
• R01 AG034982 NIA NIH HHS
• R01 NS042857 NINDS NIH HHS
• P01 AG21190 NIA NIH HHS
• K23 AR051315 NIAMS NIH HHS
• R01 NS42857 NINDS NIH HHS

• Adolescent
• Adult
• Analgesia/methods
• Double-Blind Method
• Female
• Humans
• Male
• Middle Aged
• Pain/diagnosis
• Pain/physiopathology
• Pain Management
• Placebo Effect
• Transcutaneous Electric Nerve Stimulation/methods
• Young Adult

• R03 NR010405 NINR NIH HHS
• UL1 RR024979 NCRR NIH HHS
• 5 UL1RR024979-3 NCRR NIH HHS
• R03NR010405 NINR NIH HHS

• Cold Temperature
• Humans
• Models, Biological
• Pain/physiopathology
• Pain Measurement/instrumentation
• Pain Measurement/methods
• Pain Threshold

• clinical trials
• experimental pain
• opioids

• Analgesics, Opioid/administration & dosage
• Analgesics, Opioid/adverse effects
• Analgesics, Opioid/pharmacokinetics
• Drug Administration Schedule
• Humans
• Models, Biological
• Pain/drug therapy
• Pain Measurement
• Pain Threshold/drug effects
• Randomized Controlled Trials as Topic

• Administration, Cutaneous
• Adult
• Analgesics, Opioid/administration & dosage
• Analgesics, Opioid/adverse effects
• Analgesics, Opioid/pharmacology
• Buprenorphine/administration & dosage
• Buprenorphine/adverse effects
• Buprenorphine/pharmacology
• Cold Temperature
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Electric Stimulation
• Female
• Fentanyl/administration & dosage
• Fentanyl/adverse effects
• Fentanyl/pharmacology
• Hot Temperature
• Humans
• Immersion
• Male
• Pain/physiopathology
• Pain Measurement/methods
• Pain Measurement/standards
• Sensitivity and Specificity

• Adult
• Analgesics/therapeutic use
• Electric Stimulation
• Hot Temperature
• Humans
• Models, Biological
• Muscles
• Pain Measurement
• Physical Stimulation
• Reproducibility of Results
• Skin
• Viscera

Methods related to experimental human pain research aim at activating different nociceptors, evoke pain from different organs and activate specific pathways and mechanisms. The different possibilities for using mechanical, electrical, thermal and chemical methods in visceral pain research are discussed with emphasis of combinations (e.g., the multimodal approach). The methods have been used widely in assessment of pain mechanisms in the esophagus and have contributed to our understanding of the symptoms reported in these patients. Hence abnormal activation and plastic changes of central pain pathways seem to play a major role in the symptoms in some patients with gastro-esophageal reflux disease and in patients with functional chest pain of esophageal origin. These findings may lead to an alternative approach for treatment in patients that does not respond to conventional medical or surgical therapy.

• Pain
• Gut
• Experimental
• Chest pain
• Esophagitis

• Central Nervous System/physiopathology
• Chest Pain/etiology
• Chest Pain/physiopathology
• Electric Stimulation
• Esophagogastric Junction/innervation
• Gastroesophageal Reflux/complications
• Gastroesophageal Reflux/physiopathology
• Hot Temperature
• Humans
• Ischemic Preconditioning
• Mechanotransduction, Cellular
• Models, Theoretical
• Pain/etiology
• Pain/physiopathology
• Signal Transduction/physiology
• Stimulation, Chemical

Understanding and characterization of pain and other sensory symptoms are among the most important issues in the diagnosis and assessment of patient with gastrointestinal disorders. Methods to evoke and assess experimental pain have recently developed into a new area with the possibility for multimodal stimulation (e.g., electrical, mechanical, thermal and chemical stimulation) of different nerves and pain pathways in the human gut. Such methods mimic to a high degree the pain experienced in the clinic. Multimodal pain methods have increased our basic understanding of different peripheral receptors in the gut in health and disease. Together with advanced muscle analysis, the methods have increased our understanding of receptors sensitive to mechanical, chemical and temperature stimuli in diseases, such as systemic sclerosis and diabetes. The methods can also be used to unravel central pain mechanisms, such as those involved in allodynia, hyperalgesia and referred pain. Abnormalities in central pain mechanisms are often seen in patients with chronic gut pain and hence methods relying on multimodal pain stimulation may help to understand the symptoms in these patients. Sex differences have been observed in several diseases of the gut, and differences in central pain processing between males and females have been hypothesized using multimodal pain stimulations. Finally, multimodal methods have recently been used to gain more insight into the effect of drugs against pain in the GI tract. Hence, the multimodal methods undoubtedly represents a major step forward in the future characterization and treatment of patients with various diseases of the gut.

• Pain
• Gut
• Experimental
• Allodynia
• Hyperalgesia
• Neurophysiology

• Abdominal Pain/physiopathology
• Afferent Pathways/physiology
• Analgesics/therapeutic use
• Animals
• Electric Stimulation
• Esophagus/physiopathology
• Gastrointestinal Diseases/drug therapy
• Gastrointestinal Diseases/physiopathology
• Gastrointestinal Tract/physiopathology
• Humans
• Pain/physiopathology
• Physical Stimulation
• Sensation/physiology
• Sex Characteristics
• Spinal Cord/physiopathology

• Analgesics, Opioid/therapeutic use
• Animals
• Behavior, Animal
• Codeine/therapeutic use
• Disease Models, Animal
• Male
• Methadone/therapeutic use
• Morphine/therapeutic use
• Motor Activity/drug effects
• Motor Activity/physiology
• Pain/drug therapy
• Pain/etiology
• Pain Measurement/methods
• Pain Threshold/drug effects
• Rats
• Rats, Sprague-Dawley
• Reaction Time/drug effects
• Rotarod Performance Test/methods
• Sciatic Neuropathy/drug therapy
• Spinal Cord Injuries/complications
• Time Factors

• Analgesics, Opioid/pharmacology
• Animals
• Behavior, Animal/physiology
• Chronic Disease
• Dose-Response Relationship, Drug
• Female
• Male
• Pain/physiopathology
• Pain Measurement
• Pain Threshold
• Rats
• Rats, Inbred F344
• Reaction Time
• Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
• Sex Factors
• Time Factors

• DA07244 NIDA NIH HHS
• DA10277 NIDA NIH HHS

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Cold Temperature/adverse effects
• Depressive Disorder/physiopathology
• Depressive Disorder/therapy
• Electroconvulsive Therapy
• Emotions/physiology
• Female
• Humans
• Male
• Middle Aged
• Pain/physiopathology
• Pain/psychology
• Pain Management
• Pain Measurement
• Pain Threshold/physiology
• Pain Threshold/psychology
• Pressure/adverse effects
• Reaction Time/physiology
• Treatment Outcome

• Analgesics/metabolism
• Analgesics/pharmacokinetics
• Animals
• Drug Resistance/genetics
• Female
• Gonadal Steroid Hormones/metabolism
• Humans
• Male
• Menstrual Cycle/physiology
• Pain/genetics
• Pain/physiopathology
• Pain/psychology
• Pain Threshold/physiology
• Sex Characteristics
• Uterus/innervation
• Uterus/physiopathology
• Visceral Afferents/physiology

• Algorithms
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Anticonvulsants/adverse effects
• Anticonvulsants/therapeutic use
• Antidepressive Agents, Tricyclic/adverse effects
• Antidepressive Agents, Tricyclic/therapeutic use
• Humans
• Nervous System Diseases/complications
• Nociceptors/anatomy & histology
• Nociceptors/drug effects
• Nociceptors/physiology
• Pain/drug therapy
• Pain/etiology
• Randomized Controlled Trials as Topic
• Selective Serotonin Reuptake Inhibitors/adverse effects
• Selective Serotonin Reuptake Inhibitors/therapeutic use

• Analgesics/therapeutic use
• Drug Evaluation/methods
• Drug Evaluation/standards
• Humans
• Models, Biological
• Muscles/physiopathology
• Pain/drug therapy
• Pain/etiology
• Pain/physiopathology
• Pain Measurement/methods
• Pain Threshold
• Physical Stimulation/methods
• Skin/physiopathology
• Stimulation, Chemical
• Viscera/physiopathology

• Adult
• Analysis of Variance
• Cold Temperature/adverse effects
• Female
• Humans
• Male
• Pain Measurement/methods
• Pressure
• Sex Characteristics
• Surveys and Questionnaires
• Temperature