Long-term intraspinal infusions of opioids in the treatment of neuropathic pain. [Intrathecal opioids in chronic non-malignant pain: relief and life quality]. Opioid therapy for chronic noncancer back pain. A randomized prospective study. Long-term oral opioid therapy in patients with chronic nonmalignant pain. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial. The effect of opioids on phantom limb pain and cortical reorganization. Long-term management of noncancer pain with transdermal therapeutic system-fentanyl. Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review. A Prospective, Randomized Trial of Intrathecal Injection vs. Epidural Infusion in the Selection of Patients for Continuous Intrathecal Opioid Therapy. Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-controlled trial and long-term evaluation. A prospective study of long-term intrathecal morphine in the management of chronic nonmalignant pain. Oral opioid therapy for chronic peripheral and central neuropathic pain. Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. Patient-controlled analgesia for mucositis pain in children: a three-period crossover study comparing morphine and hydromorphone. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. A randomized, double-blind, double-dummy, crossover trial comparing the safety and efficacy of oral sustained-release hydromorphone with immediate-release hydromorphone in patients with cancer pain. Canadian Palliative Care Clinical Trials Group. Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled, double-blind crossover study. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Intrathecal opioid treatment for chronic non-malignant pain: a 3-year prospective study. Placebo and naloxone can alter post-surgical pain by separate mechanisms.
Long-term intraspinal infusions of opioid drugs are being increasingly utilized in patients with noncancer pain. Despite this, there is a lack of long-term information, including success and failure rates for pain relief and technical problems. During a 5-year period, 18 noncancer patients underwent implantation of programmable infusion pumps for long-term intrathecal opioid infusion. Patients had (a) neuropathic pain, (b) had failed or been ineligible for noninvasive treatments, and (c) obtained greater than 50% pain relief with intrathecal trial infusions of morphine sulfate or sufentanil citrate. A disinterested third-party reviewer evaluated patients at the most recent follow-up. Sixty-one percent (11/18) of patients had good or fair pain relief with mean follow-up 2.4 +/- 0.3 years (0.8-4.7 years). Average numeric pain scores decreased by 39% +/- 4.3%. Five of the 11 responders required lower opioid doses (12-24 mg/day morphine) and the remaining six patients required higher opioid doses (> 34 mg/day morphine). Failure of long-term pain relief occurred in 39% (7/18) despite good pain relief in trial infusions and the use of both morphine and sufentanil. Technical problems developed in 6/18 patients but appeared to be preventable with further experience. Long-term intrathecal opioid infusions can be effective in treatment of neuropathic pain but might require higher infusion doses. The use of opioids for treatment of non-malignant pain is controversial. The evaluation of pain relief and of the quality of life of 11 severely incapacitated chronic non-cancer pain patients treated with long term intrathecal infusion of opioids trought implantable pumps was performed. The mean duration of pain complaints was 5.3 years. The mean pain intensity was 8.6. In 7 patients, pain episodes lasted at least 6 hours daily. The mean duration of the therapy was 19.6 months. After the treatment the mean pain score became 3.9. In only 1 patient, the duration of pain episodes was still longer than 6 hours. Quality of life improved in 36.36% of the cases. The long term spinal opioids through implantable pumps for non-malignant pains results in pain relief but not necessarily improves the quality of life. A randomized, open, long-term, repeated-dose comparison of an anti-inflammatory drug and two opioid regimens in 36 patients with back pain.
                To examine the long-term safety and efficacy of chronic opioid therapy in a randomized trial of patients with back pain.
                All participants underwent a 4-week washout period of no opioid medication before being randomly assigned to one of three treatment regimens for 16 weeks: 1) naproxen only, 2) set-dose oxycodone, or 3) titrated-dose oxycodone and sustained-release morphine sulfate. All patients then were assigned to a titrated dose of opioids for 16 weeks and then gradually tapered off their medication for 12 weeks. Finally, all participants were monitored for a 1-month posttreatment washout period. Each patient was called once a week for a report on pain, activity, mood, medication, hours awake, and adverse effects and was monitored carefully for signs of abuse and noncompliance.
                Weekly reports during the experimental phase showed the titrated-dose group to have less pain (P < 0.001) and less emotional distress (P < 0.001) than the other two groups. Both opioid groups were significantly different from the naproxen-only group. During the titration phase, patients also reported significantly less pain and improved mood. Few differences were found in activity or hours asleep, or between average pretreatment and posttreatment phone-interview and questionnaire variables. No adverse events occurred, and only one participant showed signs of abuse behavior.
                The results suggest that opioid therapy has a positive effect on pain and mood but little effect on activity and sleep. Opioid therapy for chronic back pain was used without significant risk of abuse. However, tapered-off opioid treatment is palliative and without long-term benefit. In contrast to the use of opioids for the treatment of acute and chronic cancer pain, the administration of chronic opioid therapy for pain not due to malignancy remains controversial. We describe 100 patients who were chronically given opioids for treatment of nonmalignant pain. Most patients experienced neuropathic pain or back pain. We used sustained-release dihydrocodeine, buprenorphine, and sustained-release morphine. Pain reduction was measured with visual analogue scales (VAS), and the Karnofsky Performance Status Scale was used to assess the patient's function. Good pain relief was obtained in 51 patients and partial pain relief was reported by 28 patients. Only 21 patients had no beneficial effect from opioid therapy. There was a close correlation between the sum and the peak VAS values (r = 0.983; p less than 0.0001) and pain reduction was associated with an increase in performance (p less than 0.0001). The most common side effects were constipation and nausea. There were no cases of respiratory depression or addiction to opioids. Our results indicate that opioids can be effective in chronic nonmalignant pain, with side effects that are comparable to those that complicate the treatment of cancer pain. The aim of the present study has been to assess the responsiveness of various types of chronic pain to opioids given i.v. and tested against placebo in a double-blind, randomized fashion. Pain classified as primary nociceptive was effectively alleviated (P greater than 0.001) while neuropathic deafferentation pain was not significantly influenced by morphine or equivalent doses of other opioids. Also 'idiopathic' pain, defined as chronic pain with no or little demonstrable pathology, failed to respond. The results were not related to whether the patients were regular users of narcotic analgesics or not. The outcome of our double-blind opioid test has proved useful to justify a continued, or discontinued, use of narcotic medication in individual patients. It may also support the indication and choice of invasive stimulation procedures (spinal cord or brain). The results of the study illustrate the misconception of chronic pain as an entity and highlight the importance of recognizing different neurobiological mechanisms and differences in responsiveness to analgesic drugs as well as to non-pharmacological modes of treatment. The opioid test has thus become a valuable tool in pain analysis and helpful as a guide for further treatment. Pancreatic cancer is an aggressive tumor associated with high mortality. Optimal pain control may improve quality of life (QOL) for these patients.
                To test the hypothesis that neurolytic celiac plexus block (NCPB) vs opioids alone improves pain relief, QOL, and survival in patients with unresectable pancreatic cancer.
                Double-blind, randomized clinical trial conducted at Mayo Clinic, Rochester, Minn. Enrolled (October 1997 and January 2001) were 100 eligible patients with unresectable pancreatic cancer experiencing pain. Patients were followed up for at least 1 year or until death.
                Patients were randomly assigned to receive either NCPB or systemic analgesic therapy alone with a sham injection. All patients could receive additional opioids managed by a clinician blinded to the treatment assignment.
                Pain intensity (0-10 numerical rating scale), QOL, opioid consumption and related adverse effects, and survival time were assessed weekly by a blinded observer.
                Mean (SD) baseline pain was 4.4 (1.7) for NCPB vs 4.1 (1.8) for opioids alone. The first week after randomization, pain intensity and QOL scores were improved (pain intensity, P< or =.01 for both groups; QOL, P<.001 for both groups), with a larger decrease in pain for the NCPB group (P =.005). From repeated measures analysis, pain was also lower for NCPB over time (P =.01). However, opioid consumption (P =.93), frequency of opioid adverse effects (all P>.10), and QOL (P =.46) were not significantly different between groups. In the first 6 weeks, fewer NCPB patients reported moderate or severe pain (pain intensity rating of > or =5/10) vs opioid-only patients (14% vs 40%, P =.005). At 1 year, 16% of NCPB patients and 6% of opioid-only patients were alive. However, survival did not differ significantly between groups (P =.26, proportional hazards regression).
                Although NCPB improves pain relief in patients with pancreatic cancer vs optimized systemic analgesic therapy alone, it does not affect QOL or survival. The efficacy of oral retarded morphine sulphate (MST) was tested against placebo in a double-blind crossover design in 12 patients with phantom limb pain after unilateral leg or arm amputation. Two counterbalanced treatment phases of 4 weeks each were initiated with an intravenous test infusion of MST or Placebo. The titration phase was 2 weeks. The dose of MST was titrated to at least 70 mg/day and at highest 300 mg/day. Pain intensity was assessed hourly on visual analog scales during a 4-week treatment-free phase, both treatment phases and at two follow-ups (6 and 12 months). Reorganization of somatosensory cortex, electric perception and pain thresholds as well as selective attention were measured pre- and post-treatment. A significant pain reduction was found during MST but not during placebo. A clinically relevant response to MST (pain reduction of more than 50%) was evident in 42%, a partial response (pain reduction of 25-50%) in 8% of the patients. Neuromagnetic source imaging of three patients showed initial evidence for reduced cortical reorganization under MST concurrent with the reduction in pain intensity. Perception and pain thresholds were not significantly altered whereas attention was significantly lower under MST. Thus, opioids show efficacy in the treatment of phantom limb pain and may potentially influence also cortical reorganization. These data need to be replicated in larger patient samples. Transdermal therapeutic system-fentanyl (TTS-F) has been extensively studied in cancer pain management. However, few studies have addressed the long-term management of noncancer pain, especially when it relates to neuropathic pain. A total of 529 patients were recruited into this prospective open-label study to determine the safety and effectiveness of TTS-F in relation to quality-of-life (QOL) stratified according to pain type and etiology. TTS-F significantly improves QOL within 28 days, and pain management within 48 hours. The frequency of side effects rapidly decreases over time, and patients not experiencing adequate pain management are identified within 28 days. The median duration of therapy for effective pain management was 10 months, and 90% of patients sustained such efficacy. TTS-F offers statistically significant increases in QOL-Short Form 12 (including the Physical Component Scale and Mental Component Scale measures) and pain control (Greek Brief Pain Inventory) from one time point to the next (P <.0001). These improvements are not influenced by pain type or etiology. TTS-F is a safe and effective pain management system independent of patient characteristics and demographic factors. What is of most importance is that in those patients with neuropathic pain, for whom opioids have long been thought to be ineffective, similar effectiveness is demonstrated when compared to patients with nociceptive pain. We evaluated the efficacy and tolerability of opioids in the long-term management of chronic noncancer pain. This retrospective chart review included 86 outpatients who started receiving, between 1994 and 1998, long-acting opioids. For each patient, the number of different opioids used and the efficacy and tolerability of each opioid prescribed were noted. During a mean follow-up of 8.8 +/- 6.3 mo, the number of opioids used by each patient was 2.3 +/- 1.4. Patient diagnoses were: back pain (31), neuropathy (20), joint pain (13), visceral pain (7), reflex sympathetic dystrophy (7), headache (5), fibromyalgia (3). The first opioid prescribed was effective for 36% of patients, was stopped because of side effects in 30%, and was stopped for ineffectiveness in 34%. Of the remaining patients, the second opioid prescribed after the failure of the first was effective in 31%, the third in 40%, the fourth in 56%, and the fifth in 14%. There was one case of addiction and no case of tolerance. We conclude that if it is necessary to change the opioid prescription because of intolerable side effects or ineffectiveness, the cumulative percentage of efficacy increases with each new opioid tested. Failure of one opioid cannot predict the patient's response to another. Implications: This study showed that if a patient receiving chronic opioid therapy experiences an intolerable side effect or if the drug is ineffective, changing to a different opioid may result in a lessening or elimination of the side effect and/or improved analgesia. The objective of this study was to compare the cost and safety of intrathecal injection (IN) vs. epidural infusion (CE) trial and to provide a preliminary assessment of the prognostic value of each in the selection of patients for long-term continuous intrathecal opioid therapy (CIOT). Thirty-seven patients with chronic nonmalignant pain who were being considered for CIOT were randomized to morphine trial by IN or CE. Analgesic response and complications were monitored throughout trial. Sixty-seven percent of IN (12/18) and 79% (15/19) of CE subjects reported good pain relief (defined as ≥ 50% pain reduction) and were implanted with a permanent infusion system. Eighty-nine percent (24/27) of subjects provided six-month CIOT follow-up data. Cost of trial and health care utilization during six months of CIOT were compared between groups. Analgesic and functional response during CIOT was also compared between IN and CE groups. The cost of IN trial was significantly less than CE trial (p < 0.001). Complications were generally mild in both groups, although opioid-related side effects tended to be more common in the IN group. Successful pain relief after six months of CIOT was reported by 10 (60%) and 14 (64%) patients who underwent IN and CE trial, respectively (p = 0.32; Fisher's exact test). There was no difference between IN and CE groups in McGill Pain rating, quality of life (VAS), mood (Profile of Mood States), or function (Sickness Impact Profile) after six months of CIOT. We conclude that intrathecal injection is a safe procedure for use in selection of patients for CIOT and is less costly than epidural infusion. Differences in pain and functional response to long-term opioids among patients selected by either trial method are not large. Although opioid analgesics have well-defined efficacy and safety in treatment of chronic cancer pain, further research is needed to define their role in treatment of chronic noncancer pain.
                To evaluate the effects of controlled-release oxycodone (OxyContin tablets) treatment on pain and function and its safety vs placebo and in long-term use in patients with moderate to severe osteoarthritis pain.
                One hundred thirty-three patients experiencing persistent osteoarthritis-related pain for at least 1 month were randomized to double-blind treatment with placebo (n = 45) or 10 mg (n = 44) or 20 mg (n = 44) of controlled-release oxycodone every 12 hours for 14 days. One hundred six patients enrolled in an open-label, 6-month extension trial; treatment for an additional 12 months was optional.
                Use of controlled-release oxycodone, 20 mg, was superior (P<.05) to placebo in reducing pain intensity and the interference of pain with mood, sleep, and enjoyment of life. During long-term treatment, the mean dose remained stable at approximately 40 mg/d after titration, and pain intensity was stable. Fifty-eight patients completed 6 months of treatment, 41 completed 12 months, and 15 completed 18 months. Common opioid side effects were reported, several of which decreased in duration as therapy continued.
                Around-the-clock controlled-release oxycodone therapy seemed to be effective and safe for patients with chronic, moderate to severe, osteo-arthritis-related pain. Effective analgesia was accompanied by a reduction in the interference of pain with mood, sleep, and enjoyment of life. Analgesia was maintained during long-term treatment, and the daily dose remained stable after titration. Typical opioid side effects were reported during short- and long-term therapy. To examine in a prospective manner the long-term safety and efficacy of chronic intrathecal morphine in patients with severe, nonmalignant pain refractory to less invasive modalities.
                Forty patients with severe, chronic nonmalignant pain poorly managed by systemic medications were identified as candidates for intraspinal trial of morphine. Thirty participants reported successful pain relief during trial and were implanted with an intraspinal delivery system. Standardized measures of pain and functional status were assessed before treatment was begun and at defined intervals during the subsequent 24 months. Intrathecal opioid use and pharmacological and device-related complications were also monitored.
                The participants had a mean age of 58 +/- 13 years and a mean pain duration of 8 +/- 9 years. Fifty-three percent of the study participants were women. Pain type was characterized as mixed neuropathic-nociceptive (15 of 30 patients, 50%), peripheral neuropathic (10 of 30 patients, 33%), deafferentation (4 of 30 patients, 13%), or nociceptive (1 of 30 patients, 3%). Forty-seven percent of the patients were diagnosed with failed back surgery syndrome. Significant improvement over baseline levels of visual analog scale pain was measured at each follow-up examination after implant. Overall, 50% (11 of 22 patients) of the population reported at least a 25% reduction in visual analog scale pain after 24 months of treatment. In addition, the McGill Pain Questionnaire, visual analog scale measures of functional improvement and pain coping, and several subscales of the Chronic Illness Problem Inventory showed improvement throughout the follow-up period. Pharmacological side effects were managed medically by morphine dose reduction, addition of bupivacaine, or replacement of morphine with hydromorphone. Device-related complications requiring repeat operations were experienced by 20% of the patients.
                Continuous intrathecal morphine can be a safe, effective therapy for the management of severe, nonmalignant pain among a carefully selected patient population and can result in long-term improvement in several areas of daily function. Although opioids are commonly used to treat chronic neuropathic pain, there are limited data to guide their use. Few controlled trials have been performed, and many types of neuropathic pain remain unstudied.
                Adults with neuropathic pain that was refractory to treatment were randomly assigned to receive either high-strength (0.75-mg) or low-strength (0.15-mg) capsules of the potent mu-opioid agonist levorphanol for eight weeks under double-blind conditions. Intake was titrated by the patient to a maximum of 21 capsules of either strength per day. Outcome measures included the intensity of pain as recorded in a diary, the degree of pain relief, quality of life, psychological and cognitive function, the number of capsules taken daily, and blood levorphanol levels.
                Among the 81 patients exposed to the study drug, high-strength levorphanol capsules reduced pain by 36 percent, as compared with a 21 percent reduction in pain in the low-strength group (P=0.02). On average, patients in the high-strength group took 11.9 capsules per day (8.9 mg per day) and patients in the low-strength group took close to the 21 allowed (18.3 capsules per day; 2.7 mg per day). Affective distress and interference with functioning were reduced, and sleep was improved, but there were no differences between the high-strength group and the low-strength group in terms of these variables. Noncompletion of the study was primarily due to side effects of the opioid. Patients with central pain after stroke were the least likely to report benefit.
                The reduction in the intensity of neuropathic pain was significantly greater during treatment with higher doses of opioids than with lower doses. Higher doses produced more side effects without significant additional benefit in terms of other outcome measures.
                Copyright 2003 Massachusetts Medical Society Patients with cancer frequently experience episodes of acute pain, i.e., breakthrough pain, superimposed on their chronic pain. Breakthrough pain is usually treated with short-acting oral opioids, most of which provide some relief after 15-20 minutes, with peak effects after 30-45 minutes. Oral transmucosal fentanyl citrate (OTFC), a unique formulation of the opioid fentanyl, has been shown to provide meaningful pain relief within 5 minutes in patients following surgery. We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of OTFC for cancer-related breakthrough pain.
                Patients who were 18 years of age or older, receiving the equivalent of at least 60 mg oral morphine or at least 50 microg transdermal fentanyl per day for chronic cancer-related pain, and experiencing at least one episode of breakthrough pain per day were studied. After titration to an effective OTFC dose, subjects were given 10 randomly ordered treatment units (seven OTFC units and three placebo units) in the form of identical lozenges. If acceptable pain relief was not achieved within 30 minutes, subjects were instructed to take their previous breakthrough pain medication (i.e., rescue medication). Pain intensity, pain relief, and use of rescue medication were evaluated at 15-minute intervals over a 60-minute period.
                Eighty-nine of 92 patients who received the randomized treatment were assessable (i.e., treated with at least one unit of OTFC and one unit of placebo). OTFC produced significantly larger changes in pain intensity and better pain relief than placebo at all time points (two-sided P<.0001). Episodes treated with placebo required the use of rescue medication more often than episodes treated with OTFC (34% versus 15%; relative risk = 2.27; 95% confidence interval = 1.51-3.26; two-sided P<.0001).
                OTFC appears effective in the treatment of cancer-related breakthrough pain. (1) To test the safety and efficacy of a clinical protocol for administering opioid by using patient-controlled analgesia (PCA) for the management of mucositis pain in children after bone marrow transplantation, (2) to compare the efficacy, side-effect profile, and potency ratio of morphine with those of hydromorphone by using PCA as the method of opioid administration, and (3) to obtain pharmacokinetic data on hydromorphone and morphine in this population of children.
                In this double-blind, three-period crossover study, patients were randomly assigned to receive either morphine (group 1) or hydromorphone (group 2) initially by means of PCA on days 1, 2, and 3 (period 1), to be followed on days 4, 5, and 6 (period 2) with the alternative opioid, followed by the opioid used at the commencement of the study on days 7, 8, and 9 (period 3). A clinical protocol for calculating the PCA commencement opioid dose and subsequent opioid-dose escalation was tested by measures of safety and efficacy. Measures of pain intensity and opioid side effects were made during the three periods. On the last study day (day 10), patients received a continuous infusion of opioid derived from the previous 24-hour PCA opioid requirement, and blood specimens were collected and stored for subsequent opioid analysis.
                Ten patients were enrolled in this study. Rapid escalation in opioid requirement commonly occurred at the commencement of PCA, followed by a variable plateau phase and then deescalation of opioid requirement after mucositis resolution. The measures demonstrated the safety and efficacy of the clinical protocol. In the concentrations used, there was no statistical difference between the mean daily pain, sedation, nausea and vomiting, and pruritus scores for both opioids (Friedman test). The analysis of variance of the log-total opioid doses per patient during periods 1, 2, and 3 indicated that patients used 27% more hydromorphone than expected from its presumed 7:1 ratio relative to morphine potency used in the PCA infusions. The mean plasma hydromorphone concentration was 4.7 ng/ml (range, 1.9 to 8.9 ng/ml), and the mean clearance was 51.7 ml/min per kilogram of body weight (range, 28.6 to 98.2 ml/min per kilogram). The mean plasma morphine, morphine-6-glucuronide, and morphine-3-glucuronide concentrations were 40.0 ng/ml (range, 15 to 62.5), 168.2 ng/ml (range, 54.4 to 231.9), and 391.0 ng/ml (range, 149.4 to 921.7), respectively. The mean morphine clearance was 34.3 ml/min per kilogram of body weight (range, 19.3 to 58.3). The mean molar ratios of morphine-6-glucuronide/morphine, morphine-3-glucoronide/morphine, and morphine-3-glucuronide/morphine-6-glucuronide were 2.48 (range, 1.4 to 3.3), 5.82 (range, 3.4 to 9.1), and 2.46 (range, 1.1 to 3.3), respectively.
                The safety and efficacy of a clinical protocol for the administration of opioids by means of PCA for mucositis pain after bone marrow transplantation was demonstrated. In this small study, hydromorphone was not superior to morphine in terms of analgesia or the side-effect profile: a larger study would be needed to show a difference. The clearances of hydromorphone and morphine in the children studied were generally greater than those previously recorded, but this finding may be related to disease or treatment variables. Apart from clearance, the morphine pharmacokinetics in the study population were similar to those previously recorded. Hydromorphone may be less potent in this population of children than indicated by adult equipotency tables. Tricyclic antidepressants (TCA) provide less than satisfactory pain relief for postherpetic neuralgia (PHN), and the role of opioids is controversial.
                To compare the analgesic and cognitive effects of opioids with those of TCA and placebo in the treatment of PHN.
                Seventy-six patients with PHN were randomized in a double-blind, placebo-controlled, crossover trial. Each subject was scheduled to undergo three treatment periods (opioid, TCA, and placebo), approximately 8 weeks' duration each. Doses were titrated to maximal relief or intolerable side effects. The primary outcome measures were pain intensity (0 to 10 scale), pain relief (0 to 100%), and cognitive function. Analyses included patients who provided any pain ratings after having received at least a single dose of a study medication.
                Fifty patients completed two periods, and 44 patients completed all three. Mean daily maintenance doses were morphine 91 mg or methadone 15 mg and nortriptyline 89 mg or desipramine 63 mg. Opioids and TCA reduced pain (1.9 and 1.4) more than placebo (0.2; p < 0.001), with no appreciable effect on any cognitive measure. The trend favoring opioids over TCA fell short of significance (p = 0.06), and reduction in pain with opioids did not correlate with that following TCA. Treatment with opioids and TCA resulted in greater pain relief (38 and 32%) compared with placebo (11%; p < 0.001). More patients completing all three treatments preferred opioids (54%) than TCA (30%; p = 0.02).
                Opioids effectively treat PHN without impairing cognition. Opioids and TCA act via independent mechanisms and with varied individual effect. To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study.
                Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia.
                One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity.
                A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded. To evaluate the safety and efficacy of a new slow-release preparation of hydromorphone (SRH) in the treatment of cancer pain.
                Ninety-five adult patients from three Canadian Palliative Care Centers with no evidence of mental impairment received treatment for cancer pain with an oral opioid analgesic. After informed consent was obtained, patients underwent titration to a stable dose of immediate-release hydromorphone (IRH) for 48 hours, and were then randomized to receive IRH or SRH for 5 days in a double-blind basis. During day 6, a crossover took place, and patients received the alternate drug for 5 days. Pain intensity was assessed using a visual analog scale (VAS) and ordinal scale (OS). Side effects were assessed using VAS. Patients and investigators made a blinded global rating of efficacy a blinded final choice between SRH and IRH.
                In 75 assessable patients, pain intensity of the VAS and OS were (mean +/- SD) 27 +/- 21 and 1.3 +/- 0.6 on IRH, versus 29 +/- 21 (P = .13) and 1.3 +/- 0.6 (P = .19) on SRH, respectively. The total number of extra doses of opioids, global rating, and final blinded choice by both patients and investigators were not significantly different between IRH and SRH. Differences in side effects were not significant.
                Our findings suggest that SRH is as safe and effective as IRH in the treatment of cancer pain. Amitriptyline is the most common analgesic adjuvant used in cancer patients with neuropathic pain, even though no specific studies have demonstrated a benefit. A randomized placebo-controlled, double-blind crossover study was designed to evidence the effects of amitriptyline in patients with neuropathic cancer pain.
                Sixteen advanced cancer patients with neuropathic pain on systemic morphine therapy, no longer receiving oncologic treatment, presenting moderate pain (about 4 or more, but less than 7, on a numerical scale of 0-10) in the last week, and given a stable morphine dose in the last 2 days were admitted to the study. During the first week of study, patients were administered 25 mg of amitriptyline or equivalent drops of placebo at night for 3 days and 50 mg for the following 4 days. Doses for patients aged more than 65 years were 15 mg (first 3 days) and 30 mg (3 days after). After a week, a crossover took place for the second week, with the other treatment at an inverse sequence. Opioid consumption, pain intensity, symptoms and adverse effects, mood, sleep, patient's preference, quality of life before starting the study, the first week after and the second week after were recorded.
                No significant benefits in analgesia were found in the global pain intensity of the previous week of treatment, the least pain intensity or the pain evaluated just after a week of treatment, at the moment of the visit, when amitriptyline was compared with placebo. A significant difference was evidenced for the worst pain (P < 0.035). No differences in opioid doses during the period of study were found. Drowsiness, confusion and dry mouth were significantly more intense with amitriptyline than with placebo (P < 0.036, 0.003, and 0.034, respectively). There were no substantial differences between the two treatments in Spitzer's quality of life score and for each item. No differences in patients' preference for the two treatment periods were found. The analgesic effects of amitriptyline were slight and associated with adverse effects.
                In light of the results obtained in the study, the extensive use of the drug for cancer pain should be questioned. Painful neuropathy is one of the most common long-term complications of diabetes mellitus and often proves difficult to relieve.
                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.
                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).
                CR oxycodone is effective and safe for the management of painful diabetic neuropathy and improves QOL. Forty-three patients with peripheral neuropathic pain, exclusively pain reduced by spinal cord stimulation (SCS), were switched into a painful state after SCS inactivation. This mode was used to assess the pain-relieving effect of carbamazepine (CMZ) and opioids in a double-blinded, placebo-controlled trial. In Phase 1, the patients were randomly allocated to receive either CMZ (600 mg/d) or placebo during an SCS-free period of 8 days. In Phase 2, after a CMZ elimination interval of 7 days, 38 patients received either sustained-release morphine (90 mg/d) or placebo for 8 days. In cases of intolerable pain, the patients were authorized to reactivate their SCS. The pain intensity was rated on a numeric analog scale. In 38 patients who completed Phase 1, significant delay in pain increase was observed in the CMZ group as compared with placebo (P = 0.038). In Phase 2, the trend observed with morphine was insignificant (P = 0.41). Two CMZ patients and one morphine patient showed complete pain relief and preferred to continue the medication. Thirty-five patients returned to SCS. We conclude that CMZ is effective in peripheral neuropathic pain. Morphine obviously requires larger individually titrated dosages than those used in this study for results to be adequately interpreted. Intrathecal (IT) opioid therapy is a treatment alternative for patients with severe chronic non-malignant pain. Several uncontrolled retrospective and prospective outcome studies have suggested a benefit in chronic non-malignant pain patients, but uncertainties about patient selection in these studies weaken the results. This study evaluated long-term outcome of IT opioid therapy in chronic non-malignant pain prospectively, and included two comparative groups to improve understanding of selection criteria and relative severity of intrathecal pump recipients (PRs). The study subjects included 38 PRs while the comparative groups included 31 intrathecal candidates who either had an unsuccessful trial, or declined the IT therapy, and another group of 41 newly referred patients. The following data were analyzed at study entry, and at 6 monthly intervals for a 3-year period: Symptom Check List 90 (SLC-90), SF-36 Health survey, Beck Depression Inventory, McGill Pain Questionnaire (short form), Oswestry Disability Index, Pain Drawings and Pain rating on visual analogue scale. Data analysis suggests the study group of PRs had improvements in pain, mood, and function from baseline to 36 months. These same parameters improved among new referrals (less severe patients receiving conservative pain management) while non-recipients significantly worsened. Although PRs improved, they were still worse off at 36 months than new referrals were at baseline. The study showed that when patients with extremely severe pain problems are selected as pump candidates, they will likely improve with the therapy, but their overall severity of pain and symptoms still remains high. The discovery of an endogenous opioid-mediated analgesic system has led to the search for its physiological roles and how it might be activated in natural conditions. Environmental and surgical stress and certain forms of transcutaneous electrical stimulation or acupuncture appear to activate this system. Several studies also suggest that this opioid system mediates placebo analgesia. Placebo reduces post-surgical pain in comparison with no treatment, and this analgesia is apparently reversed by the opioid antagonist, naloxone. However, these studies did not indicate whether naloxone and placebo exert their effects by common or by separate mechanisms. By administering hidden infusions of naloxone (in subjects unaware that the medication was being given) separate from the administration of a placebo, we were able to assess the effects of these two treatments independently. We report here evidence that placebo analgesia can occur after blockade of opioid mechanisms by naloxone and that naloxone can produce hyperalgesia independent of the placebo effect. The combined action of these effects is sufficient to explain the reversal of placebo analgesia by naloxone.
Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain, whereas intermediate-term studies demonstrate significant efficacy of opioids over placebo, which is likely to be clinically important. Reported adverse events of opioids are common but not life threatening. Further randomized controlled trials are needed to establish long-term efficacy, safety (including addiction potential), and effects on quality of life.