Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society.

Neuropathic pain (NeP), generated by disorders of the peripheral and central nervous system, can be particularly severe and disabling. Prevalence estimates indicate that 2% to 3% of the population in the developed world suffer from NeP, which suggests that up to one million Canadians have this disabling condition. Evidence-based guidelines for the pharmacological management of NeP are therefore urgently needed. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment are based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Analgesic agents recommended for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Recommended fourth-line treatments include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy, such as lamotrigine, topiramate and valproic acid. Treatment must be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Further studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes, and treatment of pediatric and central NeP.

Chronic noncancer pain and the long term utility of opioids.

OBJECTIVE: To report on a long term experience in treating patients with chronic noncancer pain (CNCP). METHODS: One hundred two patients with CNCP were seen every three months and followed for one year or more (median eight years, range one to 22). Demographic data, diagnostic categories and response to therapies were recorded. The utility and safety of opioid therapy, adverse events, impact on disability and issues related to previous psychiatric or chemical dependency history were documented. RESULTS: Most patients reported a variety of neuropathic pain problems and most required chronic opioid therapy after the failure of other treatments. Although 44% reported being satisfied with pain relief despite adverse events, it is noteworthy that the remaining patients chose to continue therapy for the modest benefit of pain relief despite adverse events. Moreover, 54% were less disabled on opioid therapy. CONCLUSIONS: This is a large sample of CNCP patients, most taking opioids over a long period of time. CNCP can be treated by opioids safely and with a modest effect, with improvement in functioning in some patients who are refractory to other measures. If care is taken, opioids may even be used effectively for patients with a history of chemical dependency.

Naratriptan efficacy in migraineurs who respond poorly to oral sumatriptan.

OBJECTIVES: To determine whether 347 patients would respond to a 50-mg oral dose of sumatriptan, even though they considered themselves poor responders to this acute therapy for migraine, and to investigate whether oral naratriptan can be an effective acute therapy for migraine in the subset of patients who did not respond to sumatriptan under double-blind, well-controlled conditions. BACKGROUND: Although most migraineurs respond to sumatriptan, there remains a need for an effective alternative for those who do not respond. Naratriptan is a more potent and more lipophilic member of this class of agent and could prove beneficial in such patients. This is the first well-controlled study to assess the value of another 5-HT1B/1D agonist in this difficult patient subset. METHODS: This study comprised two migraine attacks. The first (attack 1) was a single-blind assessment of the efficacy of sumatriptan (50 mg orally) in patients with a history of poor response to the drug. The second (attack 2) was a randomized, parallel group, double-blind, placebo-controlled trial of naratriptan (2.5 mg orally) in nonresponders to oral sumatriptan. RESULTS: Attack 1: About two thirds of this selected migraine population did not respond to sumatriptan. Attack 2: Naratriptan was statistically superior to placebo for headache relief at 2 hours and 4 hours, as well as for most other features of migraine attacks. These data suggest an intrinsic efficacy of naratriptan in this patient subset and not a coincidental response. No unexpected tolerability issues arose. CONCLUSIONS: Naratriptan is an alternative therapy for migraineurs who respond poorly to oral sumatriptan. No response to one "triptan" does not necessarily predict no response to them all.

The treatment of neuropathic pain: antidepressants and opioids.

OBJECTIVE: The objective of this article was to review the positive scientific data on antidepressants and opioids, which are largely confined to randomized controlled trials in two neuropathic pain conditions that have proved to be good models for clinical investigation. These two disorders are postherpetic neuralgia and painful diabetic neuropathy. DESIGN: This is a review of the literature using MEDLINE, CINAHL, and the Cochrane Database. RESULTS: There is extensive literature supporting the use of the older antidepressants such as amitriptyline in neuropathic pain. Newer randomized controlled trials support the use of opioids. CONCLUSIONS: First-line therapy for neuropathic pain may be either an older generation antidepressant such as amitriptyline or nortriptyline or the anticonvulsant gabapentin. For refractory cases, chronic opioid therapy may be the only avenue of relief, and evidence is accumulating that this approach is safe if proper guidelines are observed.

Migraine polypharmacy and the tolerability of sumatriptan: a large-scale, prospective study.

Polypharmacy (the prescription of more than one therapy for a single patient) and subcutaneous (s.c.) sumatriptan tolerability were prospectively studied in 12,339 migraineurs, each followed for up to 1 year. Inclusion/exclusion criteria were minimal and mirrored United States Imitrex labeling. Drug usage and compliance monitoring were automatically interfaced with prescription refill. Concomitant drugs were used by 79% of patients, with analgesics, antidepressants, and sedatives used most commonly. No adverse interactions between sumatriptan and neurological drugs were found, possibly reflecting relative inability of the former to cross the blood-brain barrier. No difference in cardiovascular adverse events was associated with oral contraceptive use, which was more common than expected. No other drug class influenced adverse event probability, although sample sizes for these comparisons was sometimes <400 patients. This study confirms the prevalence of polypharmacy in migraine, identifies the drugs used, and concludes that, on a population basis, the tolerability of s.c. sumatriptan, when used according to labeled instructions, is unaffected by these concomitant drugs.

Postherpetic neuralgia: the importance of preventing this intractable end-stage disorder.

An argument is presented here for postherpetic neuralgia as an intractable end-stage disorder for many patients. The exciting possibility of prevention of this disorder by early, aggressive treatment exists; however, the extent to which therapy can be effective is unknown. Early, aggressive treatment of the pain of herpes zoster is, nevertheless, urged, and the options for treatment are discussed. These options include antiviral therapy within the first 72 h, if possible, from the onset of rash or radicular pain and the use of analgesics, including opioids (if necessary), nerve blocks, and early antidepressant therapy. In addition, the extent to which vaccination of older adults will prevent postherpetic neuralgia is unknown but appears to hold promise.

Nortriptyline versus amitriptyline in postherpetic neuralgia: a randomized trial.

UNLABELLED: OBJECTIVE (BACKGROUND): Amitriptyline (AT) is a standard therapy for postherpetic neuralgia (PHN). Our hypothesis was that nortriptyline (NT), a noradrenergic metabolite of AT, may be more effective. METHODS: A randomized, double-blind, crossover trial of AT versus NT was conducted in 33 patients. RESULTS: Thirty-one patients completed the trial. Twenty-one of 31 (67.7%) had at least a good response to AT or NT, or both. We found no difference with regard to relief of steady, brief, or skin pain by visual analog scales for pain and pain relief; mood; disability; satisfaction; or preference between the two drugs. Intolerable side effects were more common with AT. Most patients (26/33) were not depressed, and most responding showed no change in rating scales for depression despite the occurrence of pain relief. CONCLUSIONS: We concluded that this study provides a scientific basis for an analgesic action of NT in PHN because pain relief occurred without an antidepressant effect, and that although there were fewer side effects with NT, AT and NT appear to have a similar analgesic action for most individuals.

Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia.

OBJECTIVE: Although opioid analgesics are used in the management of neuropathic pain syndromes, evidence of their efficacy remains to be established. We evaluated the clinical efficacy and safety of oxycodone in neuropathic pain using postherpetic neuralgia as a model. METHODS: Patients with postherpetic neuralgia of at least moderate intensity were randomized to controlled-release oxycodone 10 mg or placebo every 12 hours, each for 4 weeks, using a double-blind, crossover design. The dose was increased weekly up to a possible maximum of 30 mg every 12 hours. Pain intensity and pain relief were assessed daily, and steady (ongoing) pain, brief (paroxysmal) pain, skin pain (allodynia), and pain relief were recorded at weekly visits. Clinical effectiveness, disability, and treatment preference were also assessed. RESULTS: Fifty patients were enrolled and 38 completed the study (16 men, 22 women, age 70+/-11 years, onset of postherpetic neuralgia 31+/-29 months, duration of pain 18+/-5 hours per day). The oxycodone dose during the final week was 45+/-17 mg per day. Compared with placebo, oxycodone resulted in pain relief (2.9+/-1.2 versus 1.8+/-1.1, p=0.0001) and reductions in steady pain (34+/-26 versus 55+/-27 mm, p=0.0001), allodynia (32+/-26 versus 50+/-30 mm, p=0.0004), and paroxysmal spontaneous pain (22+/-24 versus 42+/-32 mm, p=0.0001). Global effectiveness, disability, and masked patient preference all showed superior scores with oxycodone relative to placebo (1.8+/-1.1 versus 0.7+/-1.0, p=0.0001; 0.3+/-0.8 versus 0.7+/-1.0, p=0.041; 67% versus 11%, p=0.001, respectively). CONCLUSIONS: Controlled-release oxycodone is an effective analgesic for the management of steady pain, paroxysmal spontaneous pain, and allodynia, which frequently characterize postherpetic neuralgia.

The treatment of postherpetic neuralgia.

Postherpetic neuralgia, when defined as neuropathic pain persisting 1 month or longer after herpes zoster infection, affects about 10% of all patients who have contracted the disease. The incidence of postherpetic neuralgia increases with age; at age 60, about 50% of herpes zoster patients will suffer significant pain, and this proportion grows with subsequent decades. If therapy is carefully chosen and monitored, it is possible to give satisfactory relief, taking pain from severe to mild, to between 60 and 70% of patients. This article will review current treatment and focus on antidepressant drugs, treatments that are contentious and of current interest such as topical agents, and the use of opioids for this type of chronic neuropathic pain.

Topical capsaicin as an adjuvant analgesic.

Topical capsaicin has been studied in a variety of conditions by uncontrolled and controlled trials. It is attractive because it is a simple, safe treatment. Although these studies suggest an analgesic effect, even placebo-controlled trials have been impossible to blind due to the burning sensation induced by the capsaicin. A high placebo response rate in the controlled trials is an interesting observation and may account for the apparent salutary effect reported in the studies lacking a control. A careful scrutiny of the results of these trials to date as well as clinical experience indicate at best a modest effect with the currently available preparations with many patients failing to find relief, finding the relief unsatisfactory, or being unable to tolerate the burning sensation. Occasional patients appear to have a very good result, and these unusual cases may not be reflected by clinical trials. Topical capsaicin is generally not satisfactory as a sole therapy for chronic painful conditions, although it may serve as an adjuvant to other approaches.

Antidepressant drugs as adjuvant analgesics.

This article reviews the history of the use of antidepressants in painful states and traces the evolution of thinking from initially considering them as antidepressants to the current concept that they have an analgesic action. The greatest part of this paper considers chronic, nonmalignant, painful states and the evidence with each for the efficacy of some of these drugs. The mechanism of action, pharmacokinetics and adverse effects are discussed. Practical suggestions are made regarding their usage. Although antidepressants are imperfect analgesics because of limited efficacy and untoward effects, they may be the only avenue of relief for a painful condition. The correct choice of agent and proper administration are critical.

A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia.

A large double-blind, vehicle-controlled study of 143 patients with chronic postherpetic neuralgia (PHN) was performed to evaluate the degree of efficacy of topically applied capsaicin 0.075% cream. In addition, the safety and efficacy of long-term application of topical capsaicin in PHN was assessed by following patients in an open-label study for up to 2 years. In the double-blind phase, 143 patients with PHN of 6 months' duration or longer were enrolled. Since epidemiologic studies of patients who receive no treatment have shown that only 10% to 25% of those with PHN after 1 month will still have pain at 1 year, two separate efficacy analyses were performed: one with all evaluable patients (n = 131) and the other with 93 patients whose PHN lasted for longer than 12 months prior to study startup. All efficacy variables, including the physician's global evaluation of reduction in PHN pain, changes in pain severity on the categoric scale, visual analogue scale for pain severity, visual analogue scale for pain relief, and functional capacity scale, showed significant improvement at nearly all time points throughout the study for both patient groups, based on duration of PHN pain. In contrast, the group receiving vehicle cream remained essentially unchanged. Data from the long-term, open-label phase (up to 2 years, n = 77), which immediately followed the 6-week blinded phase, showed that the clinical benefit in patients treated for a short (6-week) period with topical capsaicin could be maintained or amplified in most patients (86%) during prolonged therapy. There were no serious adverse effects observed or reported throughout the trial; in fact, the only side effect associated with capsaicin treatment was the burning or stinging at local sites of application (in 9% of patients) during exposures of up to 2 years (long-term phase). On the basis of these data, we conclude that capsaicin 0.075% cream is a safe and effective treatment for the pain of postherpetic neuralgia and should be considered for initial management of patients with this condition.

Post-herpetic neuralgia: further post-mortem studies of cases with and without pain.

The pathological features associated with post-herpetic neuralgia require further study. We report here 5 cases, 3 with severe post-herpetic neuralgia (PHN) and 2 with no persistent pain. The findings of dorsal horn atrophy and cell, axon and myelin loss with fibrosis in the sensory ganglion were found only in patients with persistent pain. Marked loss of myelin and axons in the nerve and/or sensory root were found in cases with and without pain. Some evidence is presented for a more generalized subacute or chronic inflammatory process which may explain the clinical features of some patients. Further studies will be necessary to fully describe the morbid anatomy of this disorder.

The post-mastectomy pain syndrome and the effect of topical capsaicin.

Eighteen patients with the post-mastectomy pain syndrome (PMPS) form the basis of this study. PMPS probably occurs in a minority of women after mastectomy. The onset of persistent pain usually occurred immediately or very shortly after the operation. The pain location or sensory findings implied involvement of the territories of other cutaneous branches of the intercostal nerves as well as the intercostobrachial nerve. A variety of treatment approaches were unsatisfactory. Twelve of 14 patients completing treatment with topical 0.025% capsaicin showed improvement after 4 weeks and 8 (57%) were judged to be good or excellent responses. Six months after the trial's completion 50% of those followed continued to have good pain relief. This therapy should now be subjected to a randomized, double-blind, placebo-controlled trial.

Postherpetic neuralgia.

Postherpetic pain persisting 1 month or longer occurs in only a small percentage of all patients with herpes zoster. In most patients, PHN tends to diminish with time. The incidence is, however, directly related to age. Any therapeutic claim for prophylaxis or treatment of PHN has to be evaluated with these observations in mind. There is some information about the pathologic features and a concept of the pathogenesis can be suggested. There is evidence for an imbalance in fiber input (reduced large, inhibitory fibers, and intact or increased small, excitatory fibers) to an abnormal dorsal horn that may contain hypersensitive neurons. Prevention of PHN remains difficult. There is evidence that systemic steroids exert a preventive effect when employed in the treatment of herpes zoster in the immunocompetent patient. A reasonable regimen is 60 mg of prednisone tapered over 10 to 14 days. One double-blind, controlled study supports the use of amantadine in this situation; this drug is an option in patients for whom steroids are contraindicated, such as those with peptic ulcer, diabetes mellitus or compromised immune function. The dosage of amantadine used in this study was 100 mg twice daily for a month. Although a number of other therapies have been suggested, these remedies remain in need of further, more scientific study. For established PHN, there is firm support for the reduction of pain from severe to mild in two thirds of patients administered low doses of amitriptyline followed by gradual, small increments. In the age group over 65 years, one may use as small a dose as 10 mg with an increase of 10 mg every 5 to 7 days. In those younger than 65, a dose of 25 mg to start is reasonable, with increments of 25 mg. Although unproved, the addition of a phenothiazine, such as fluphenazine, may provide further pain relief. Preliminary studies also indicate that topical capsaicin may be a useful new treatment. Although widely used, there is no good evidence for the use of anticonvulsants alone in this disorder. Studies of local anesthetic sprays with vibration and continuous TENS are uncontrolled, but these modalities may be of some merit. One uncontrolled study reported benefit from epidural steroids. DREZ lesions are a possibility in failed medical cases, but other surgical procedures appear to be of little or no use. Although the measures described here will benefit a number of patients, PHN remains an intractable problem in some cases.(ABSTRACT TRUNCATED AT 400 WORDS)

Post-herpetic neuralgia: post-mortem analysis of a case.

The morphological and biochemical substrates of the severe pain in post-herpetic neuralgia (PHN) are unclear. This report is an autopsy study of a 67-year-old male with severe PHN during the last 5 years of his life over the right T7-8 dermatomes. The dorsal horn of the thoracic spinal cord of the affected side was atrophic from T4 to T8, with loss of both myelin and axons. Despite this, only the T8 ganglion was affected by fibrosis and cell loss and only the nerve roots at that level appeared affected. Markers of unmyelinated afferents (substance P), substantia gelatinosa neurons (opiate receptors), glial cells (glial fibrillary acidic protein), and descending spinal projections (dopamine-beta-hydroxylase and serotonin) were not different at affected versus non-affected spinal cord levels. The pain of PHN may result from the uninhibited activity of unmyelinated primary afferents as a result of the loss of myelinated afferent fibers and the possible presence of hypersensitive neurons in the dorsal horn.