Treatment considerations for patients with neuropathic pain and other medical comorbidities.

The efficacy of drugs for neuropathic pain has been established in randomized controlled trials that have excluded patients with comorbid conditions and those taking complex medications. However, patients with neuropathic pain frequently present with complex histories, making direct application of this evidence problematic. Treatment of neuropathic pain needs to be individualized according to the cause of the pain, concomitant diseases, medications, and other individual factors. Tricyclic antidepressants (TCAs), gabapentinoids, selective noradrenergic reuptake inhibitors, and topical lidocaine are the first-line choices; if needed, combination therapy may be used. When a new drug is added, screening for potential drug interactions is recommended. The TCAs have anticholinergic adverse effects and may cause orthostatic hypotension. They should be avoided or used cautiously in patients with cardiac conduction disturbances or arrhythmias. Patients who lack cytochrome P450 2D6 isoenzyme activity are prone to adverse effects of TCAs and venlafaxine and have a weaker analgesic response to tramadol. A combination of several serotoninergic drugs may lead to serotonin syndrome. Risk of gastrointestinal tract bleeding is increased in patients taking selective serotonin reuptake inhibitors or venlafaxine, especially when combined with nonsteroidal anti-inflammatory drugs. Dose adjustment may be needed in patients with renal or hepatic impairment. Depending on the drug, the dose is reduced or the dosage interval lengthened. Slow titration and careful follow-up are needed. No drug is absolutely safe during pregnancy and lactation. Particular care must be exercised during the first trimester when drug dose should be as low as possible. Individual weighing of benefits and risks should guide therapeutic decisions.

Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.

The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

Advances in opioid pharmacology.

Natural and synthetic opioid compounds, either alone or in combination with other drugs, are widely used analgesics for patients with both acute and chronic pain. Decades of extensive pharmacologic investigations have characterized three high-affinity cell-surface neuronal receptors, the activation of which is responsible for both the desirable properties (antinociception) and undesirable properties (respiratory depression, nausea and vomiting, dependence, etc.) of opioid drugs. Recent research in molecular biology and pharmacogenetics in relation to opioids and their receptors has helped clarify previous pharmacologic observations and has laid the groundwork for new analgesic therapies with improved therapeutic outcomes.

Management of chronic intractable angina - spinal opioids offer an alternative therapy.

The successful treatment of chronic intractable angina by spinally administered opioids via an Algomed drug delivery device (hereinafter called the pump) is reported in seven patients. All patients had at least two prior cardiac surgeries and the duration of minimally controlled chronic intractable angina varied from 5 to 19 years prior to spinally administered opioids. The duration of effective spinally administered analgesia to either the epidural (two cases) or intrathecal (five cases) spaces varied from 2 to 7 years. The opioid used was either morphine or fentanyl and the dose increase (either mg/year or microg/year, respectively) varied from 1.2 to 16. We suggest that bolus spinal morphine or fentanyl administered via the pump is a viable alternative for the effective control of angina when more established therapies have been found to provide insufficient pain relief.

Utility assessments of opioid treatment for chronic pain.

OBJECTIVE: The primary study objective was to assess preferences for pain treatment outcomes among patients with cancer and noncancer chronic pain. A secondary objective was to assess their quality of life. METHODS: Patients with cancer or noncancer chronic pain completed an interview using a computer to estimate utilities, or preference ratings, for health states related to pain treatment. The interview was devised using conjoint analysis methodology. Health states were characterized by four attributes (effectiveness of pain control, side effects, side effect severity, and opioid route of administration) and their levels, and each was assumed to last for a 14-day period. Participants also completed health-related quality of life and demographic questionnaires. RESULTS: Mean preference ratings for participants with noncancer chronic pain (N = 96) ranged from a high of 0.87 (well-controlled pain with no side effects) to a low of 0.18 (poorly controlled pain with severe mood changes/alterations, severe respiratory depression, or severe vomiting). Mean preference ratings for participants with cancer pain (N = 25) were similar and ranged from a high of 0.89 (well-controlled pain with no side effects) to a low of 0.19 (poorly controlled pain with severe respiratory depression or severe vomiting). Results confirmed previous findings that chronic pain has a severe, multidimensional impact on patients, and that the quality of life of persons with chronic pain is among the lowest observed for any medical condition. CONCLUSIONS: This study provides a valuable assessment, from the patient's perspective, of the balance between treatment tolerability and manifestation of disease symptoms. Heightened awareness of patients' preferences for treatment outcomes may lead to improved selection of treatments, better adherence, and ultimate treatment success.

Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain.

Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin.

Ketamine as an adjunct to morphine in the treatment of pain.

A double-blind multidose trial of the addition of ketamine (0-40 mg, i.m., 8 times per day) to intramuscular morphine therapy was undertaken in a 61-year-old man with chronic back pain related to osteoporosis who had received inadequate pain relief from anterior interbody fusion, dorsal column stimulation and morphine alone. The patient reported only mild side effects. Nausea, tiredness and well-being were not significantly influenced by the ketamine dose level. Visual analogue pain scores prior to each dose were not associated with the ketamine dose level, but pain scores 30 min after doses were significantly reduced in a dose-related manner. In addition, the amount of morphine used by the patient was significantly reduced as the ketamine dose increased. This patient experienced substantial benefit from the addition of ketamine to intramuscular morphine therapy.

Chronopharmacokinetic variability in plasma morphine concentrations following oral doses of morphine solution.

Twenty-six patients with severe pain associated with cancer were entered into a study where they were required to take morphine mixture for 7 days. Prior to this, their morphine dose had been optimised to provide the most favourable balance between pain relief and side effects. After 6 days of taking their optimised morphine dose at 4-hourly intervals, the patients were admitted to the Pain Management Unit such that the doses from 18:00 h on day 6 were taken under direct nursing supervision. Frequent blood samples were collected after the 10:00 h (dose 1), 14:00 h (dose 2) and 18:00 h (dose 3) on day 7. There was a significant difference between the 3 doses with respect to Cmax values for morphine with dose 3 > dose 1 > dose 2. Further, there was considerable variability in the percentage change of either dose 1 or dose 3 Cmax values relative to dose 2. The Cmax values of the active metabolite morphine-6-glucuronide (M6G), measured in 6 of the patients, for the 3 dosing intervals followed a similar trend to the parent drug, but only doses 1 and 2 differed significantly. Similar but less pronounced changes were observed in the area-under-curve parameter calculated for both morphine and M6G during the 3 dosing intervals. There were no significant differences in the Cmin or Tmax parameters for either morphine or M6G between the 3 dosing intervals. These results suggest intra-individual variation in the absorption of morphine or changes in the volume of distribution during the day.(ABSTRACT TRUNCATED AT 250 WORDS)

CT contrast evidence of injectate encapsulation after long-term epidural administration.

This case report provides radiographic evidence (CT scan with Iopamidol) to support the development of epidural injectate encapsulation in response to long-term epidural morphine injections via an implanted polyurethane catheter. The patient complained of intense low interscapular pain when the catheter was used for administration of epidural morphine for control of angina. The patient had previously enjoyed 3 months of excellent pain relief following the initiation of epidural morphine via an implanted portal device. The CT scan, with contrast dye injected via the epidural catheter, clearly showed loculation of the injectate and associated indentation of the spinal cord. It is significant to note that the dye in the encapsulated sheath occupied a significant proportion of the spinal canal extending from T7 to T9.