BACKGROUND Pelvic cancers such as cancer of the cervix can spread locally to involve adjacent structures such as the lumbosacral plexus and the sympathetic chain. When this happens the prognosis is usually poor. An early suspicion of recurrence may result in investigation leading to earlier and better treatment. A physical sign that may be an early and only sign of recurrence is described. OBJECTIVE To report the late Dr Ramon Evans' unpublished case series of the hot foot syndrome due to (mostly malignant) retroperitoneal disease. This unique contribution is an opportunity to pay tribute to a man who was a meticulous recorder of the patient narrative and practitioner of a detailed and comprehensive physical examination. METHODS A longitudinal, observational, retrospective, descriptive study is reported. Data were collected from a convenience sample of 86 patients, 75 of whom had retroperitoneal cancer and 11 of whom were diagnosed with other conditions in that area. Patients referred to the Smythe Pain Clinic were seen at both the Princess Margaret Hospital and Toronto General Hospital in Toronto, Ontario, in the 1970s. They were referred with intractable pain in the leg or back and often a history of a treated abdominal or pelvic cancer in the previous months or years. Baseline demographic data were collected including age, sex, diagnosis, pain location, characteristics and severity, physical findings, investigations and mortality. RESULTS The 86 subjects comprised 27 men and 59 women. Carcinoma of the cervix was the most common tumour. Most had a presenting complaint of leg pain. Neurological physical signs were demonstrated in the lower extremities in 44%; however, 56%(48 patients) had only an ipsilateral, warm, dry 'hot foot' due to sympathetic deafferentation. The prognosis for the underlying illness was poor for the malignant group. DISCUSSION Sympathetic interruption by cancer is well known in apical lung cancer as the tumour spreads upwards to involve the inferior brachial plexus. An analogous situation occurs as cancers, such as that of the cervix, spread laterally to invade the lumbosacral plexus and sympathetic chain. Signs of sympathetic deafferentation (the 'hot foot') may be the earliest and only sign in this situation. This sign may be missed unless it is anticipated and a thorough physical examination carried out. CONCLUSION Evans' sign is important because it may be an early and solitary sign of retroperitoneal recurrence of pelvic (cervix, rectum, bladder, ovary and prostate) cancers. Recognition of this finding when intractable pain in the back and leg occurs with a history of this type of cancer could lead to earlier and more successful treatment.

OBJECTIVES: The history behind the current understanding of the varicella-zoster virus and its relationship to the pain conditions caused by shingles and postherpetic neuralgia are reviewed. The framework for the current conceptualization is Hope-Simpson's latency hypothesis. Data from recent work in virology, neuroanatomy and epidemiology are reviewed, as is work using varicella-zoster virus-infected animals. The recent data largely confirm Hope-Simpson's hypothesis and extend it significantly.

This article reports the relief of severe causalgia of the right infra-orbital nerve by nerve section and re-location in a 14-year-old boy who had worsening neuropathic pain (NP) and was housebound and refractory to all analgesics for 14 months. His infra-orbital nerve was sectioned and re-located into his buccal fat pad. Severe steady burning, electric shock-like pain and allodynia disappeared and he was able to return to school and an increasingly normal life at one year post-operatively and is pain-free at 3 years and 6 months of follow-up. With NP further deafferentation can cause a worsening of the pain or anaesthesia dolorosa. In this instance there was dramatic and then sequential, gradual and complete resolution of all components of this particular form of NP. Therefore, in selected patients with causalgia this nerve re-location technique may help in symptom resolution and improve quality of life.

OBJECTIVE:: The purpose of this study was to evaluate the efficacy of controlled-release (CR) tramadol and immediate-release (IR) tramadol in patients with moderate or greater intensity chronic noncancer pain. METHODS:: A total of 122 patients underwent washout from all opioids 2 to 7 days before randomization to 1 of 2 groups: active CR tramadol 200 mg every morning plus placebo IR tramadol 50 mg every 4 to 6 hours PRN rescue, or placebo CR tramadol 200 mg every morning plus active IR tramadol 50 mg every 4 to 6 hours PRN rescue. After 2 weeks, the doses were increased to CR tramadol 400 mg or placebo and IR tramadol 100 mg every 4 to 6 hours PRN or placebo, as rescue. After 4 weeks in the first phase, patients crossed over to the alternative treatment for another 4 weeks. Pain intensity (100-mm visual analog scale [VAS] and 5-point ordinal scales) was assessed twice daily in diaries. Pain intensity, Pain and Disability Index (PDI; 0-10 ordinal scale), Pain and Sleep Questionnaire (100-mm VAS), and analgesic effectiveness (7-point ordinal scale) were assessed at biweekly clinic visits. RESULTS:: Sixty-five patients (35 men, 30 women) completed the study. Mean (SD) age was 56.5 (12.7) years; mean (SD) weight was 82.0 (18.5) kg. Daily diary pain intensity (mean [SD]) was significantly lower in the CR tramadol group than in the IR tramadol group in the last 2 weeks of each phase (completers: VAS, 29.9 [20.5] vs 36.2 [20.4] mm, P < 0.001; ordinal scale, 1.41 [0.7] vs 1.64 [0.6], P < 0.001; intent-to-treat [ITT] population: VAS, 32.5 [22.9] vs 38.6 [21.2] mm, P < 0.003; ordinal scale, 1.50 [0.8] vs 1.72 [0.7], P < 0.002). The overall pain intensity scores from the daily diary were also significantly better with CR tramadol for both the completers and ITT. Similar results were obtained on the biweekly VAS pain intensity questionnaire. No differences were found between treatments in total PDI or overall Pain and Sleep scores in either population. For the completers, both patients and investigators rated effectiveness higher for CR tramadol than for IR tramadol (P < 0.004 and P < 0.008 for patients and investigators, respectively). CONCLUSION:: This study reports significant improvement in pain intensity with CR tramadol as compared with IR tramadol.

This article reviews the definition, epidemiology, pathology, clinical features, and treatment of postherpetic neuralgia (PHN). Much of this information is well established. However, there is some important new information about the pathology that may shed light on the pathogenesis of this disorder. The exciting prospect exists of the prevention of PHN by vaccination and by early, aggressive treatment of herpes zoster. This is important because current treatment approaches have significant limitations. We now have certain antidepressants, anticonvulsants, opioids, and the topical agent lidocaine that have been scientifically shown by randomized controlled trials to be effective in this disorder. However, all of these have a modest effect at best and newer treatments are necessary. Prevention may be very important for the 30% to 50% of the patients who either do not respond at all or do not respond well. Regional anesthetic procedures do not have a good scientific basis for either acute zoster or established PHN, but remain a reasonable alternative for some patients. This article addresses the issue of how effective the current treatments really are and gives practical guidelines for management.

Neuropathic pain, caused by various central and peripheral nerve disorders, is especially problematic because of its severity, chronicity and resistance to simple analgesics. The condition affects 2%-3% of the population, is costly to the health care system and is personally devastating to the people who experience it. The diagnosis of neuropathic pain is based primarily on history (e.g., underlying disorder and distinct pain qualities) and the findings on physical examination (e.g., pattern of sensory disturbance); however, several tests may sometimes be helpful. Important pathophysiologic mechanisms include sodium-and calcium-channel upregulation, spinal hyperexcitability, descending facilitation and aberrant sympathetic-somatic nervous system interactions. Treatments are generally palliative and include conservative nonpharmacologic therapies, drugs and more invasive interventions (e.g., spinal cord stimulation). Individualizing treatment requires consideration of the functional impact of the neuropathic pain (e.g., depression, disability) as well as ongoing evaluation, patient education, reassurance and specialty referral. We propose a primary care algorithm for treatments with the most favourable risk-benefit profile, including topical lidocaine, gabapentin, pregabalin, tricyclic antidepressants, mixed serotonin-norepinephrine reuptake inhibitors, tramadol and opioids. The field of neuropathic pain research and treatment is in the early stages of development, with many unmet goals. In coming years, several advances are expected in the basic and clinical sciences of neuropathic pain, which will provide new and improved therapies for patients who continue to experience this disabling condition.

The past two decades have contributed a large body of preclinical work that has assisted in our understanding of the underlying pathophysiological mechanisms that cause chronic pain. In this context, it has been recognized that effective treatment of pain is a priority and that treatment often involves the use of one or a combination of agents with analgesic action. The current review presents an evidence-based approach to the pharmacotherapy of chronic pain. Medline searches were done for all agents used as conventional treatment in chronic pain. Published papers up to June 2005 were included. The search strategy included randomized, controlled trials, and where available, systematic reviews and meta-analyses. Further references were found in reference sections of papers located using the above search strategy. Agents for which there were no controlled trials supporting efficacy in treatment of chronic pain were not included in the present review, except in cases where preclinical science was compelling, or where initial human work has been positive and where it was thought the reader would be interested in the scientific evidence to date.

OBJECTIVE To evaluate the role of methadone in the management of intractable neuropathic noncancer pain. METHODS A case series of 50 consecutive noncancer pain patients who were seen at a tertiary care centre and treated with oral methadone for a variety of intractable neuropathic pain states. RESULTS The mean age was 52.7 years and the mean duration of follow-up was 13.9 months. Post-discectomy nerve root fibrosis, complex regional pain syndrome, peripheral neuropathy and central spinal cord pain syndromes were the most common diagnoses. Over 90% had been treated with one or more tricyclic antidepressants and anticonvulsants and a similar number had received other adjuvant analgesics. All patients had failed treatment with one or more conventional opioid analgesics (mean 2.8) at a mean maximal morphine dose of 384 mg (or equivalents) per day. Twelve patients had failed spinal cord stimulation. Nineteen patients (38%) did not tolerate initial methadone titration or thought their pain was worse on methadone. Five patients (10%) declared initial benefit but required repetitive dose escalation and eventually became non-responders. Twenty-six patients (52%) reported mild (4), moderate (15), marked (6) or complete (1) pain relief and continued on methadone at a mean maintenance dose of 159.8 mg/day for a mean duration of 21.3 months. Fourteen patients (28%) reported improved function on methadone relative to previous treatments. CONCLUSIONS Methadone appears to have unique properties including N-methyl-D-aspartate antagonist activity that may make it especially useful in the management of intractable neuropathic pain. This observation needs to be tested in randomized, controlled trials.

Opiates lack potent analgesic efficacy in neuropathic pain although it is now generally accepted that the poor effect of these drugs reflects a reduction in their potency. Reduction of morphine antinociceptive potency was postulated to be due to the fact that nerve injury altered the activity of opioid systems or opioid specific signaling. Endogenous opioid systems were found to be represented in the regions involved in the nociception and are implicated in chronic pain. Opioid peptides biosynthesis and opioid receptors density in the nociceptive pathways and their functions change under various conditions associated with neuropathic pain following damage to the spinal cord and injury of peripheral nerves. Identification of a role of opioid systems in neuropathic pain and molecular and cellular mechanisms underlying these processes are of importance to understanding of the opioid action in neuropathic pain that will hopefully facilitate development of therapeutic strategies in which effectiveness of opioids in alleviation neuropathic pain is increased.

NMDA (N-methyl-D-aspartate) receptors are one class of ionotropic receptor for the ubiquitous excitatory neurotransmitter L-glutamate. The receptor is made up of four protein subunits combined from a larger library of proteins, which gives this receptor a great deal of variability. This explains the large number of modulatory sites, a variety of sites at which antagonists can interact, and therefore a number of potential drug targets. Sensitivity of the NMDA ion channel to ambient levels of Mg++ gives it a voltage dependence that suits a function of responding to intense synaptic activation; the ability of the channel to admit Ca++ tends to trigger long-term processes. The receptor is thereby involved in long-term physiological processes such as learning and memory as well as in pathological processes such as neuropathic pain. Separating these functions therapeutically with NMDA antagonists has been a major difficulty, and has not yet been achieved with currently-available agents. This review summarises the preclinical rationale, based on animal models, and the clinical evidence on the use of NMDA antagonists in pain states. It also summarises the details of the receptor so as to explain the rationale for targeting either specific sites on the receptor, or exploiting anatomical differences in subtype expression, so as to provide the beneficial effects of NMDA receptor block with an improved side effect profile. In particular, agents that are selective for receptors that include the NR2B subunit preclinically have a substantially better profile for treating neuropathic pain than do current NMDA antagonists; some emerging clinical evidence supports this view.

Methadone, although having been available for approximately half a century, is now receiving increasing attention in the management of chronic pain. This is due to recent research showing that methadone exhibits at least three different mechanisms of action including potent opioid agonism, N-methyl-D-aspartate antagonism and monoaminergic effects. This, along with methadone's excellent oral and rectal absorption, high bioavailability, long duration of action and low cost, make it a very attractive option for the treatment of chronic pain. The disadvantages of significant interindividual variation in pharmacokinetics, graduated dose equivalency ratios based on prerotation opioid dose when switching from another opioid, and the requirement for special exemption for prescribing methadone make it more complicated to use. The present review is intended to educate physicians interested in adding methadone to their armamentarium for assisting patients with moderate to severe pain.

Although N-methyl-D-aspartate (NMDA) receptor antagonists clearly attenuate the development of tolerance to the antinociceptive effects of opioids, it is not clear whether they also alter acute opioid-induced antinociception. The present study was designed to assess NMDA/opioid interactions in C57BL/6 mice by examining various NMDA receptor antagonists of different selectivity in combination with the mu opioid receptor agonists morphine and l-methadone. A mouse hot plate procedure was used to assess the effects of morphine (0.1 to 10.0 mg/kg) and l-methadone (0.1 to 5.6 mg/kg) alone and after pretreatment with the competitive NMDA receptor antagonist LY235959 (0.1 to 1.0 mg/kg), the glycine site NMDA receptor antagonist R(+)-HA-966 (10.0 to 56.0 mg/kg), or the polyamine site and NR2B selective NMDA receptor antagonist ifenprodil (3.2 to 10.0 mg/kg). Morphine and l-methadone produced dose- and time-dependent increases in 56 degrees C hot plate latencies. At the doses tested, the NMDA receptor antagonists produced no effect on hot plate latencies. However, when these drugs were combined with morphine, latency to respond to the hot plate was significantly increased from morphine alone. Combinations of the NMDA receptor antagonist LY235959 and l-methadone produced similar increases in hot plate latencies; however, combinations of l-methadone with R(+)-HA-966 or ifenprodil did not increase hot plate latencies compared with l-methadone alone. These results suggest that a range of NMDA receptor antagonists potentiate morphine-induced antinociception, although the potentiation of l-methadone might be specific to the antagonist examined. PERSPECTIVE: The inclusion of low-dose NMDA receptor antagonists to opioids might be beneficial for the treatment of acute pain by enhancing the antinociceptive effects of the opioid.

Controversy persists in relation to the analgesic efficacy of opioids in neuropathic pain. In the present study the effects of acute, subcutaneous administration of the mu-opioid receptor agonists morphine, methadone and codeine were examined in rat models of peripheral and central neuropathic pain. In the spared nerve injury (SNI) and chronic constriction injury (CCI) models of peripheral neuropathic pain, both morphine (6mg/kg) and methadone (3mg/kg) attenuated mechanical allodynia, mechanical hyperalgesia and cold allodynia for up to 1.5h post-injection (P<0.05); codeine (30mg/kg) minimally alleviated mechanical hypersensitivity in SNI, but not CCI rats. When administered to rats with photochemically-induced spinal cord injury (SCI), morphine (2 and 6mg/kg) and methadone (0.5-3mg/kg) robustly attenuated mechanical and cold allodynia for at least 2h post-injection (P<0.05). Codeine (10 and 30mg/kg) also attenuated mechanical and cold allodynia in this model for at least 3h after injection. The magnitude of opioid-mediated antinociception was similar between SNI, SCI and non-injured rats as measured in the tail flick test. At antinociceptive doses, no motor impairment as determined by the rotarod test was observed. The therapeutic window (based on antiallodynia versus ataxia) obtained for codeine, was vastly superior to that obtained with morphine or methadone in SNI and SCI rats. Furthermore, the therapeutic window for codeine in SCI rats was 4-fold greater than in SNI rats. Our results further support the efficacy of mu-opioid receptor agonists in alleviating signs of neuropathic pain in animal models of peripheral and especially central nerve injury.