Causalgia: A Review of Nerve Resection, Amputation, Immunotherapy, and Amputated Limb CRPS II Pathology.

BACKGROUND: Causalgia and complex regional pain syndrome (CRPS) type II with nerve injury can be difficult to treat. Surgical peripheral nerve denervation for causalgia has been largely abandoned by pain clinicians because of a perception that this may aggravate a central component (anesthesia dolorosa). METHODS: We selectively searched Pubmed, Cochrane, MEDLINE, EMBASE, CINAHL Plus, and Scopus from 1947 for articles, books, and book chapters for evidence of surgical treatments (nerve resection and amputation) and treatment related to autoimmunity and immune deficiency with CRPS. RESULTS: Reviews were found for the treatment of causalgia or CRPS type II (n = 6), causalgia relieved by nerve resection (n = 6), and causalgia and CRPS II treated by amputation (n = 8). Twelve reports were found of autoimmunity with CRPS, one paper of these on associated immune deficiency and autoimmunity, and two were chosen for discussion regarding treatment with immunoglobulin and one by plasma exchange. We document a report of a detailed and unique pathological examination of a CRPS type II affected amputated limb and related successful treatment with immunoglobulin. CONCLUSIONS: Nerve resection, with grafting, and relocation may relieve uncomplicated causalgia and CRPS type II in some patients in the long term. However, an unrecognized and treatable immunological condition may underly some CRPS II cases and can lead to the ultimate failure of surgical treatments.

Opioids in chronic noncancer pain: more faces from the crowd.

BACKGROUND: The use of opioids for chronic noncancer pain (CNCP) remains very controversial. There are several randomized controlled trials, mostly in neuropathic pain, reporting efficacy and safety in the short term, but more long-term data are needed. Randomized controlled trials may be limited in providing data about the patients who benefit from often high-dose opioids over the long term. The present article provides details of these patients and adds to a previous case series. METHODS: The present article contains 17 case reports of 11 CNCP conditions (followed to 2011) selected to illustrate specific issues from a survey of 84 patients with intractable CNCP treated with opioids and followed every three months for a median of 11 years. The previous published survey of this group reported outcomes of pain severity, adverse effects, pain relief, satisfaction, mood, problematic opioid use, tolerance, physical dependency, functional status, health-related quality of life (HRQL), immune status and sexual function. The outcome measures for that study included a numerical rating scale for pain, the Hospital Anxiety and Depression Scale, the Brief Pain Inventory Interference Scale, the Pain Disability Index and, for HRQL, the Short-Form Health Survey 12 version 2. Most patients in the total sample reported 50% or greater relief and a moderate improvement in disability. Scores for functional status and HRQL were not severely affected. Problematic use, tolerance and serious adverse effects, including constipation, were not major issues. These selected patient reports were chosen, not to illustrate optimal results, but rather important aspects of the diagnoses, opioids and doses, the paucity of intolerable adverse effects, particular issues (concurrent addiction history, bipolar disorder and combination therapy), disease-specific and other outcomes and duration of follow-up with complex pain problems. RESULTS: Opioids were found to be safe and useful in the long term for these particular patients, as well as in the larger group from which they originated. INTERPRETATION: These 17 reports of patients with intractable CNCP treated with opioids with some success over many years puts a face on more of the participants in the larger survey of 84 subjects, suggesting that this approach is effective and safe for some patients over many years.

The hot foot syndrome: Evans' sign and the old way.

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.

The long-term safety and efficacy of opioids: a survey of 84 selected patients with intractable chronic noncancer pain.

BACKGROUND: The use of opioids for chronic noncancer pain (CNCP) remains controversial. Despite a number of randomized controlled trials showing efficacy and safety in the short term, long-term data are limited. OBJECTIVE: To survey a selected cohort of patients with intractable CNCP with regard to long-term efficacy and safety of opioids. METHODS: The present study reports long-term results from a survey of 84 patients with CNCP. The majority of patients had neuropathic pain, were treated with opioids and were followed every three months for a median of 8.4 years. Outcomes examined were pain severity, adverse effects, pain relief, satisfaction, mood, problematic opioid use, tolerance, physical dependency, functional status, health-related quality of life, immune status, sexual function, morbidity and mortality. Measures included a numerical rating scale, the Hospital Anxiety and Depression Scale, Brief Pain Inventory interference scale, Pain Disability Index and Short-Form Health Survey 12, version 2. RESULTS AND CONCLUSIONS: Both long- and short-acting opioids were reported to be effective, with few significant long-term adverse effects in many subjects in the present selected cohort. The majority of patients reported at least 50% or greater pain relief and a moderate improvement in disability. Functional status and health-related quality of life scores were not severely affected. Problematic opioid use, tolerance and serious adverse effects, including constipation, were not major issues. The authors emphasize that the results obtained in the present selected group may not be generalizable to all CNCP patients in whom opioids are being initiated.

A qualitative systematic review of head-to-head randomized controlled trials of oral analgesics in neuropathic pain.

BACKGROUND: Neuropathic pain (NP) encompasses many difficult-to-treat disorders. There are few head-to-head, comparative, randomized controlled trials (RCTs) of drugs for NP in different analgesic categories, or of different drugs within a category, despite many placebo-controlled RCTs for individual agents. Well-designed head-to-head comparative trials are an effective way to determine the relative efficacy and safety of a new drug. OBJECTIVE: To perform a systematic review of head-to-head RCTs of oral analgesics in NP. METHODS: A systematic review of RCTs involving NP patients was performed, of which head-to-head comparative trials were selected. Reference lists from published systematic reviews were searched. These studies were rated according to the Jadad scale for quality. RESULTS AND CONCLUSIONS: Twenty-seven such trials were identified. Seventeen were comparisons of different analgesics, and 10 were of different drugs within an analgesic class. Important information was obtained about the relative efficacy and safety of drugs in different categories and within a category. Some significant differences between active treatments were reported. Trial inadequacies were identified. More and improved head-to-head RCTs are needed to inform clinical choices.

Herpes zoster and postherpetic neuralgia: past, present and future.

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.

Nerve resection and re-location may relieve causalgia: a case report.

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.

A randomized, double-blind, 8-week crossover study of once-daily controlled-release tramadol versus immediate-release tramadol taken as needed for chronic noncancer pain.

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.

Neuropathic pain: a practical guide for the clinician.

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 pharmacotherapy of chronic pain: a review.

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.

Management issues of neuropathic trigeminal pain from a medical perspective.

The purpose of this article is to review the pharmacological treatment of neuropathic trigeminal pain by means of a systematic review. A number of randomized controlled trials and important historical and uncontrolled studies in trigeminal neuralgia and postherpetic neuralgia were identified. Trigeminal neuralgia is a unique neuropathic pain disorder with a specific therapy. It does not respond to the usual drugs used for other neuropathic pains. The drug therapy of trigeminal postherpetic neuralgia is similar to that of other neuropathic trigeminal pain conditions.

Evaluation of dosing guidelines for use of controlled-release codeine in chronic noncancer pain.

OBJECTIVE: The clinical utility of guidelines for conversion of patients from a combination analgesic preparation of acetaminophen 300 mg plus codeine 30 mg every 4h to 6h as needed to scheduled controlled-release (CR) codeine every 12h was evaluated. METHODS: Adult patients with chronic noncancer pain underwent a two-week evaluation on acetaminophen plus codeine, followed by eight weeks of treatment with CR codeine. Patients taking four to six tablets of acetaminophen plus codeine per day were transferred to 50 mg CR codeine every 12 h; those on seven to nine tablets were transferred to 100 mg every 12 h; those on 10 to 12 tablets were transferred to 150 mg every 12 h; and those on greater than 12 tablets were transferred to 200 mg every 12 h. Subsequent dose adjustments were permitted. Acetaminophen (325 mg) was available for rescue. Pain intensity (five-point categorical and 100 mm visual analog scale), pain related disability, adverse events and acceptability were assessed. RESULTS: Of the 140 patients enrolled, 95 completed eight weeks of treatment with CR codeine. During month 1 and month 2, the mean CR codeine daily doses were 295.7+/-119.1 mg and 390.3+/-163.4 mg, respectively. Pain scores during both CR codeine month 1 and 2 were significantly lower than on acetaminophen plus codeine (53.6+/-20.9 mm and 49.7+/-23.7 mm versus 59.6+/-17.5 mm; P=0.0003, P=0.0001, respectively). CR codeine treatment was rated as moderately or highly acceptable by 82% of patients compared with 50% for acetaminophen plus codeine (P=0.001). Only seven patients (5.9%) discontinued CR codeine treatment because of adverse events. CONCLUSION: The results confirm the safety, efficacy and patient acceptability of the initial conversion and maintenance dosing recommendations for CR codeine from a combination opioid/nonopioid analgesic.

Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy.

BACKGROUND: Painful neuropathy is one of the most common long-term complications of diabetes mellitus and often proves difficult to relieve. METHODS: Patients with diabetic neuropathy with moderate or greater pain for at least 3 months, were evaluated for efficacy, safety and health-related quality of life (QOL) while receiving controlled-release (CR) oxycodone (OxyContin) or active placebo. Patients underwent washout from all opioids 2-7 days before randomization to 10 mg CR oxycodone or active placebo (0.25 mg benztropine) q12h. The dose was increased, approximately weekly, to a maximum of 40 mg q12h CR oxycodone or 1 mg q12h benztropine, with crossover to the alternate treatment after a maximum of 4 weeks. Acetaminophen, 325-650 mg q4-6h prn was provided as rescue. RESULTS: Thirty-six patients were evaluable for efficacy (21 men, 15 women, mean age 63.0+/-9.4 years). CR oxycodone resulted in significantly lower (P=0.0001) mean daily pain (21.8+/-20.7 vs. 48.6+/-26.6 mm VAS), steady pain (23.5+/-23.0 vs. 47.6+/-30.7 mm VAS), brief pain (21.8+/-23.5 vs. 46.7+/-30.8 mm VAS), skin pain (14.3+/-20.4 vs. 43.2+/-31.3 mm VAS), and total pain and disability (16.8+/-15.6 vs. 25.2+/-16.7; P=0.004). Scores from 6 of the 8 SF-36 domains and both summary scales, Standardized Physical Component (P=0.0002) and Standardized Mental Component (P=0.0338) were significantly better during CR oxycodone treatment. The number needed to treat to obtain one patient with at least 50% pain relief is 2.6 and clinical effectiveness scores favoured treatment with CR oxycodone over placebo (P=0.0001). CONCLUSION: CR oxycodone is effective and safe for the management of painful diabetic neuropathy and improves QOL.

Postherpetic neuralgia.

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.