Mitchell B. Max

Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood

In a randomized, double-blind crossover study, 29 patients with painful diabetic neuropathy received 6 weeks of amitriptyline and 6 weeks of an “active” placebo that mimicked amitriptyline side effects. Amitriptyline was superior to placebo in relieving pain in weeks 3 through 6. Both steady, burning pain and lancinating pains were relieved. Patients able to tolerate higher amitriptyline doses reported greater relief, through the maximum dose of 150 mg nightly. Amitriptyline analgesia was similar in depressed and nondepressed subgroups and was not associated with mood improvement. We conclude that amitriptyline relieves pain in diabetic neuropathy; this effect is independent of mood elevation.

GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.

We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury–evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.

Amitriptyline, but not lorazepam, relieves postherpetic neuralgia

In a double-blind, randomized, crossover study, 58 patients with postherpetic neuralgia received 6-week courses of amitriptyline, 12.5 to 150 mg/d; lorazepam, 0.5 to 6 mg/d; or lactose placebo. Doses were titrated to the maximum level tolerated. Patients rated pain in a diary, using lists of verbal descriptors. Forty-seven percent of patients reported moderate or greater relief with amitriptyline, 16% with placebo, and 15% with lorazepam. Mean amitriptyline dose was 65 mg/d. Greater relief was associated with higher amitriptyline doses, up to the maxiumum dose of 150 mg/d, and with higher serum tricyclic levels. Lorazepam did not relieve pain and was associated with severe depressive reactions in four patients.

Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain

&NA; The oxygen‐15 water bolus positron emission tomography (PET) method was used to image regional brain activity in 4 patients with chronic post‐traumatic neuropathic pain confined to one lower limb and in 1 patient with post‐herpetic neuralgia. In comparison to 13 normal subjects, scans of the patients disclosed a statistically significant decrease in thalamic activity contralateral to the symptomatic side. Examination of the right/left ratio for all the subjects showed that the values for the patients fell at the extremes of the normal range, according to the side of the affected body part. These initial observations suggest that functional alterations in thalamic pain processing circuits may be an important component of chronic neuropathic pain.

High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia.

N-methyl-D-aspartate (NMDA) receptor antagonists relieve neuropathic pain in animal models, but side effects of dissociative anesthetic channel blockers, such as ketamine, have discouraged clinical application. Based on the hypothesis that low-affinity NMDA channel blockers might have a better therapeutic ratio, we carried out two randomized, double-blind, crossover trials comparing six weeks of oral dextromethorphan to placebo in two groups, made up of 14 patients with painful distal symmetrical diabetic neuropathy and 18 with postherpetic neuralgia. Thirteen patients with each diagnosis completed the comparison. Dosage was titrated in each patient to the highest level reached without disrupting normal activities; mean doses were 381 mglday in diabetics and 439 mglday in postherpetic neuralgia patients. In diabetic neuropathy, dextromethorphan decreased pain by a mean of 24% (95% CI: 6% to 42%, p = 0.011, relative to placebo. In postherpetic neuralgia, dextromethorphan did not reduce pain (95% CI: 10% decrease in pain to 14% increase in pain, p = 0.72). Five of 31 patients who took dextromethorphan dropped out due to sedation or ataxia during dose escalation, but the remaining patients all reached a reasonably well-tolerated maintenance dose. We conclude that dextromethorphan or other low-affinity NMDA channel blockers may have promise in the treatment of painful diabetic neuropathy.

Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli

&NA; Variations in the gene encoding catechol‐O‐methyltransferase (COMT) are linked to individual differences in pain sensitivity. A single nucleotide polymorphism (SNP) in codon 158 (val158met), which affects COMT protein stability, has been associated with the human experience of pain. We recently demonstrated that three common COMT haplotypes, which affect the efficiency of COMT translation, are strongly associated with a global measure of pain sensitivity derived from individuals’ responses to noxious thermal, ischemic, and pressure stimuli. Specific haplotypes were associated with low (LPS), average (APS), or high (HPS) pain sensitivity. Although these haplotypes included the val158met SNP, a significant association with val158met variants was not observed. In the present study, we examined the association between COMT genotype and specific pain‐evoking stimuli. Threshold and tolerance to thermal, ischemic, and mechanical stimuli, as well as temporal summation to heat pain, were determined. LPS/LPS homozygotes had the least, APS/APS homozygotes had average, and APS/HPS heterozygotes had the greatest pain responsiveness. Associations were strongest for measures of thermal pain. However, the rate of temporal summation of heat pain did not differ between haplotype combinations. In contrast, the val158met genotype was associated with the rate of temporal summation of heat pain, but not with the other pain measures. This suggests that the val158met SNP plays a primary role in variation in temporal summation of pain, but that other SNPs of the COMT haplotype exert a greater influence on resting nociceptive sensitivity. Here, we propose a mechanism whereby these two genetic polymorphisms differentially affect pain perception.

Desipramine relieves postherpetic neuralgia

Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressant agents, but its pain‐relieving potential has received little study. Other antidepressant agents—notably amitriptyline—are known to ameliorate postherpetic neuralgia, but those agents are often toxic. In a randomized double‐blind crossover design, we gave 26 postherpetic neuralgia patients 6 weeks of treatment with desipramine (mean dose, 167 mg/day) and placebo. Nineteen patients completed both treatments; 12 reported at least moderate relief with desipramine and two reported relief with placebo. Pain relief with desipramine was statistically significant from weeks 3 to 6. Psychiatric interview at entry into the study produced a diagnosis of depression for 4 patients; pain relief was similar in depressed and nondepressed patients and was statistically significant in the nondepressed group alone. We conclude that desipramine administration relieves postherpetic neuralgia and that pain relief is not mediated by mood elevation. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressant agents that have relieved neuropathic pain, may be involved in relief of postherpetic neuralgia.

Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial

&NA; Although amitriptyline relieves pain in many patients with painful diabetic neuropathy, side effects often preclude effective treatment. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressants. We compared a 6 week course of desipramine (mean dose, 201 mg/day) to active placebo in 20 patients with painful diabetic neuropathy in a double‐blind crossover trial. Pain relief with desipramine was statistically significant in weeks 5 and 6. Eleven patients reported at least moderate relief with desipramine, compared to 2 with placebo. Pain relief tended to be greater in depressed patients, but relief was also observed in patients who did not show an antidepressant effect. We conclude that desipramine relieves pain in many patients with painful diabetic neuropathy, offering an alternative for patients unable to tolerate amitriptyline. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressants proven effective in neuropathic pain, may mediate this analgesic effect.

Identifying important outcome domains for chronic pain clinical trials: An IMMPACT survey of people with pain

&NA; This two‐phase study was conducted to identify relevant domains of patient‐reported outcomes from the perspective of people who experience chronic pain. In Phase 1, focus groups were conducted to generate a pool of patient outcome‐related domains and their components. The results of the focus groups identified 19 aspects of their lives that were significantly impacted by the presence of their symptoms and for which improvements were important criteria they would use in evaluating the effectiveness of any treatment. Phase 2 was conducted to examine the importance and relevance of domains identified from a much larger and diverse sample of people with chronic pain. A survey was developed and posted on the American Chronic Pain Association website. Participants were asked to rate the importance of each item or domain identified by the focus groups on a scale of 0 to10 (i.e., 0 = “not at all important” and 10 = “extremely important”). The survey was completed by 959 individuals. The results indicate that all 19 aspects of daily life derived from the focus groups were considered important with a majority of respondents indicating a score of 8 or greater. In addition to pain reduction, the most important aspects were enjoyment of life, emotional well‐being, fatigue, weakness, and sleep‐related problems. Chronic pain clearly impacts health‐related quality of life. The results of the two phases of the study indicate that people with chronic pain consider functioning and well‐being as important areas affected by the presence of symptoms and as appropriate targets of treatment. These multiple outcomes should be considered when evaluating the efficacy and effectiveness of chronic pain treatments.

Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2).

ABSTRACT The objective of the present research was to develop a single measure of the major symptoms of both neuropathic and non‐neuropathic pain that can be used in studies of epidemiology, natural history, pathophysiologic mechanisms, and treatment response. We expanded and revised the Short‐form McGill Pain Questionnaire1 (SF‐MPQ) pain descriptors by adding symptoms relevant to neuropathic pain and by modifying the response format to a 0–10 numerical rating scale to provide increased responsiveness in longitudinal studies and clinical trials. The reliability, validity, and subscale structure of the revised SF‐MPQ (SF‐MPQ‐21) were examined in responses from 882 individuals with diverse chronic pain syndromes and in 226 patients with painful diabetic peripheral neuropathy who participated in a randomized clinical trial. The data suggest that the SF‐MPQ‐2 has excellent reliability and validity, and the results of both exploratory and confirmatory factor analyses provided support for four readily interpretable subscales—continuous pain, intermittent pain, predominantly neuropathic pain, and affective descriptors. These results provide a basis for use of the SF‐MPQ‐2 in future clinical research, including clinical trials of treatments for neuropathic and non‐neuropathic pain conditions.