Postoperative analgesia in patients with substance use disorders: Part I

The specific problems related to postoperative analgesia in patients with substance use disorders (SUD) concerning opioids, alcohol, benzodiazepines, barbiturates, cocaine, crack, amphetamines, amphetamine-like designer drugs (MDMA, ecstasy), LSD, and marijuana are described. Whereas SUD with only one substance rarely occurs, the number of polysubstance abusers is increasing. Patients with SUD may have multiple organic diseases, impaired immune response, psychiatric and behavioural abnormalities and substance-induced disorders (intoxication, withdrawal, delerium, psychotic disorders), often associated with low compliance and craving behaviour.The perioperative management should be focused on three problems: (1) on the prevention of physical withdrawal symptoms and stressful complications in patients with SUD using CNS-depressants, (2) on the symptomatic treatment of the predominant affective withdrawal symptoms in patients suffering from SUD with CNS-stimulants, and (3) on the effective pain treatment.The analgesic therapy is often difficult and required for longer periods of time than in other patients. However, the principles of multimodal analgesia are as valid as in non-addicts. To be effective, systemic analgesia with paracetamol, NSAIDs and opioids has to be adapted as usual, but regional analgesia techniques should be preferred for postoperative pain relief.Patients enrolled in preoperative maintenance programmes (methadone, buprenorphine) need their daily maintenance dose as baseline. Ths baseline therapy does not, however, induce analgesia. Therefore, these patients need additional short-acting opioids which have to be administered at higher doses than usual (which do not cause respiratory depression due to opioid tolerance). The additional opioid does not increase the risk of relapse into active SUD. On the other hand, regional analgesia in patients who are enrolled in a maintenance programme does not mean withdrawal prophylaxis. These patients have excellent analgesia, but they need their previously used maintenance opioid to prevent withdrawal. Special considerations will have to be made in patients with naltrexone.Recovering patients with a history of SUD have both an intensive fear of relapsing into the active SUD as well as fear of suffering from postoperative pain. These patients require an equally effective analgesia as other patients. Depending on the type of surgery and pain intensity they need atypical opioids (eg tramadol) or strong opioids (eg buprenorphine or morphine) as a part of balanced analgesia to the same degree as other patients. Withholding effective analgesic treatment can paradoxically lead to relapses in recovering patients. The common opinion of healthcare providers to withhold strong opioids from recovering patients with SUD is obsolete. However, in order to avoid psychotropic side effects the dosages of opioids, as well as the analgesic efficacy, should be monitored closely.     

Postoperative analgesia in patients with substance use disorders: Part II

The specific problems related to postoperative analgesia in patients with substance use disorders (SUD) concerning opioids, alcohol, benzodiazepines, barbiturates (Part I), cocaine, crack, amphetamines, amphetamine-like designer drugs (MDMA, ecstasy), LSD, and marijuana (Part II) are described. Whereas SUD with only one substance rarely occurs, the number of polysubstance abusers is increasing. Patients with SUD may have multiple organic diseases, impaired immune response psychiatric and behavioural abnormalities, and substance-induced disorders (intoxication, withdrawal, delerium, psychotic disorders), often associated with low compliance and craving behaviour.

The perioperative management should be focused on three problems: (1) on the prevention of physical withdrawal symptoms and stressful complications in patients with SUD using CNS-depressants, (2) on the symptomatic treatment of the predominant affective withdrawal symptoms in patients suffering from SUD with CNS-stimulants, and (3) on the effective pain treatment.

The analgesic therapy is often difficult and required for longer periods of time than in other patients. However, the principles of multimodal analgesia are as valid as in non-addicts. To be effective, systemic analgesia with paracetamol, NSAIDs and opioids has to be adapted as usual, but regional analgesia techniques should be preferred for postoperative pain relief.

Patients enrolled in preoperative maintenance programmes (methadone, buprenorphine) need their daily maintenance dosage as baseline. This baseline therapy does not, however, induce analgesia. Therefore, these patients need additional short-acting opioids which have to be administered at higher dosages than usual (which do not cause respiratory depression due to opioid tolerance). The additional opioid does not increase the risk of relapse into active SUD. On the other hand, regional analgesia in patients who are enrolled in a maintenance programme does not mean withdrawal prophylaxis. These patients have an excellent analgesia, but they need their previously used maintenance opioid to prevent withdrawal. Special considerations will have to be made in patients with naltrexone.

Recovering patients with a history of SUD have both an intensive fear of relapsing into the active SUD as well as fear of suffering from postoperative pain. These patients require an equally effective analgesia as other patients. Depending on the type of surgery and pain intensity they need atypical opioids (eg tramadol) or strong opioids (eg buprenorphine or morphine) as a part of balanced analgesia to the same degree as other patients. Withholding effective analgesic treatment can paradoxically lead to relapses in recovering patients. The common opinion of healthcare providers to withhold strong opioids from recovering patients with SUD is obsolete. However, in order to avoid psychotropic side effects the dosages of opioids, as well as the analgesic efficacy, should be monitored closely.     

Continuous Perioperative Sublingual Buprenorphine

Buprenorphine, a semisynthetic thebaine derivative, is a unique opioid, as it has activity at multiple receptors, including mu (partial agonist), kappa (antagonist), OLR-1 (agonist), and delta (antagonist). Because buprenorphine's pharmacology is relatively complex, misconceptions about its actions are common. Most other opioids act solely or predominately as full mu receptor agonists. Common practice at many institutions calls for the cessation of regular buprenorphine use 48–72 hours prior to surgery. This practice is based on three foundational theories that have come from scant data about the properties of buprenorphine: (1) that buprenorphine is only a partial mu agonist and therefore is not a potent analgesic; (2) because buprenorphine has a ceiling effect on respiratory depression, it also has a ceiling effect on analgesia; and (3) that buprenorphine acts as a “blockade” to the analgesic effects of other opiates when coadministered due to its strong binding affinity. However, several recent studies have called this practice into question. At our institution, we continue buprenorphine perioperatively, whenever possible, in order to provide superior pain control, discourage potentially problematic use and the more dangerous side effects of full mu agonist opiates, and avoid putting recovery at risk for those with opiate dependency issues. We present a unique case comparing two different outcomes for the same surgical course performed at two different times on the same chronic pain patient. These differences may be attributable to the variable of buprenorphine being present for one perioperative course and not the other. Pain control was easier to achieve, and functional recovery was greater when buprenorphine was maintained throughout the perioperative period when compared with using a full mu agonist opioid for chronic pain preoperatively. This is an outcome that much of the literature heretofore suggests would be unlikely. We review some aspects of buprenorphine's unique pharmacology that may explain why remaining on buprenorphine perioperatively may be preferable, which contradicts many practice guidelines.     

Opioid Interruptions,Pain, and Withdrawal Symptoms in Nursing Home Residents

PurposeInterruptions in opioid use have the potential to cause pain relapse and withdrawal symptoms. The objectives of this study were to observe patterns of opioid interruption during acute illness in nursing home residents and examine associations between interruptions and pain and withdrawal symptoms.MethodsPatients from 3 nursing homes in a metropolitan area who were prescribed opioids were assessed for symptoms of pain and withdrawal by researchers blinded to opioid dosage received, using the Brief Pain Inventory Scale and the Clinical Opioid Withdrawal Scale, respectively, during prespecified time periods. The prespecified time periods were 2 weeks after onset of acute illness (eg, urinary tract infection), and 2 weeks after hospital admission and nursing home readmission, if they occurred. Opioid dosing was recorded and a significant interruption was defined as a complete discontinuation or a reduction in dose of >50% for ≥1 day. The covariates age, sex, race, comorbid conditions, initial opioid dose, and initial pain level were recorded. Symptoms pre- and post-opioid interruptions were compared and contrasted with those in a group without opioid interruptions.FindingsSixty-six patients receiving opioids were followed for a mean of 10.9 months and experienced a total of 104 acute illnesses. During 64 (62%) illnesses, patients experienced any reduction in opioid dosing, with a mean (SD) dose reduction of 63.9% (29.9%). During 39 (38%) illnesses, patients experienced a significant opioid interruption. In a multivariable model, residence at 1 of the 3 nursing homes was associated with a lower risk of interruption (odds ratio = 0.073; 95% CI, 0.009 to 0.597; P < 0.015). In patients with interruptions, there were statistically insignificant changes in mean (SD) pain score (difference −0.50 [2.66]; 95% CI, −3.16 to 2.16) and withdrawal score (difference −0.91 [3.12]; 95% CI, −4.03 to 2.21) after the interruption as compared with before interruption. However, when compared with patients without interruptions, patients with interruptions experienced larger increases in pain scores during the follow-up periods (difference 0.09 points per day; 95% CI, −0.01 to 0.019; P = 0.08). In particular, patients who received the highest quartile of opioid dose before interruption experienced increases in pain scores over time that were 0.22 points per day larger (95% CI, 0.02 to 0.41; P = 0.03) than those without interruption. Withdrawal scores were not associated with opioid interruption regardless of dose before interruption.ImplicationsNursing home patients often experience interruptions in opioid dosing, which can be associated with worse pain, but not withdrawal symptoms, during acute illnesses. Clinicians should be aware of the potential risks and effects of opioid interruptions during acute illnesses in this patient group.     

Transdermal buprenorphine in pain management--experiences from clinical practice: Five case studies

Buprenorphine is a semi-synthetic opioid derived from thebaine. The transdermal formulation of buprenorphine has been available in Belgium for 3 years, during which time the Pain Clinic of the St Elisabeth of Verviers Hospital has gained experience in the use of transdermal buprenorphine for the treatment of moderate-to-severe pain. This paper presents four cases of chronic, non-malignant pain, and one case of chronic cancer pain. By starting patients on low doses and slowly titrating upwards, transdermal buprenorphine matrix patches provided effective analgesia and were well tolerated. Low doses of transdermal buprenorphine were created by cutting the smallest available matrix patch (35 mug/h) into halves or quarters. The initial dose was then gradually titrated upwards to the dose needed for optimum pain relief by the patients. No problems were encountered in switching patients from prior analgesic therapy with other opioids to transdermal buprenorphine.     

Oral transmucosal fentanyl citrate for the treatment of migraine headache pain in outpatients: a case series

BACKGROUND: Migraine headache pain that does not respond to traditional antimigraine medications frequently requires treatment in the emergency department (ED) with parenteral opioids. Rapid onset of pain relief in an outpatient setting for migraine headache is the primary objective of patients and clinicians. Oral transmucosal fentanyl citrate (OTFC; ACTIQ) is a novel opioid product designed to deliver rapid analgesia to patients who experience breakthrough pain (BTP). OBJECTIVE: To evaluate the effectiveness, tolerability, and patient satisfaction with OTFC for the outpatient treatment of acute, refractory migraine headache pain. PATIENTS AND METHODS: Twenty patients with recurrent acute, refractory migraine headaches who had been referred to this headache clinic are reported in this case series. All patients had a history of tolerating parenteral opioids in the ED when experiencing refractory migraine pain and had been treated with outpatient opioid therapies in attempts to manage their migraine pain. Patients were prescribed OTFC (400 microg) as rescue treatment for moderate or severe migraine headache pain as outpatients. Patients were instructed to self-administer OTFC at home and complete a diary recording: pain intensity (11-point scale; 10 = worst pain imaginable to 0 = no pain) before and 15, 30, 60, and 120 minutes after OTFC; satisfaction with the effectiveness of OTFC (selecting 1 of 7 categories ranging from "very dissatisfied" through "very satisfied") rated at 120 minutes; and adverse events. RESULTS: Eighteen patients (13 female) experienced a migraine and self-administered OTFC. OTFC successfully treated migraine episodes in all 18 outpatients; no patient went to an ED. OTFC rapidly reduced pain intensity, with significant improvement at 15 minutes that was sustained and provided progressively more pain relief at 30, 60, and 120 minutes (all P <.01). Mean (SEM) pain intensity significantly declined from 8.83 (0.35) pretreatment to 2.28 (0.67) at 120 minutes, an average reduction of 75% (P <.01). Patients' satisfaction ratings with OTFC were overwhelmingly positive, with 94% being satisfied and more than half (56%) being "very satisfied." Three (17%) patients experienced nausea, two (11%) somnolence, and one (6%) each itching, vomiting, and dry mouth. All adverse events were mild or moderate in severity. CONCLUSIONS: OTFC rapidly and significantly relieved acute, refractory migraine pain in outpatients, prevented the need for an ED visit, and was associated with high patient satisfaction ratings. The rapid onset of migraine headache pain relief in this case series is consistent with the analgesic effect reported with the use of OTFC in patients with BTP. OTFC was well tolerated in these patients who had a history of tolerating parenteral opioids in the ED when experiencing refractory migraine pain and had been treated with outpatient opioid therapies in attempts to manage their migraine pain. OTFC may be effective for outpatient treatment of acute, refractory migraine headache pain. Further controlled studies are warranted.     

Treatment of Ischemic Pain in Patients Suffering from Peripheral Vasculopathy with Transdermal Buprenorphine Plus Epidural Morphine with Ropivacaine vs. Epidural Morphine with Ropivacaine

Aim:   This study compared the efficacy and safety of buprenorphine transdermal delivery system with peridural infusion of morphine and ropivacaine to peridural infusion alone for the control of ischemic pain in patients suffering from peripheral vasculopathy.
Methods:   Eighty-six patients were randomized into two groups. In the first group, a buprenorphine patch 35 µg/hour TTDS (transtec transdermal device plus ropivacaine and morphine) was applied, and a peridural infusion of ropivacaine/morphine (200 mg + 2 mg) was established. In the second group, ropivacaine and morphine analgesia was obtained using a peridural infusion and a placebo patch. The primary efficacy parameter was the visual analog scale score for pain. Secondary parameters of efficacy were the short-form McGill Pain Questionnaire scores and a score for pain interference with sleep obtained from patient diaries evaluated every week for a period of 4 weeks.
Results:   Subjects in the TTDS group reported a reduction in pain, increased sleep, and a lower incidence of side effects compared with the control group.
Conclusion:   Transdermal buprenorphine use resulted in significant pain relief with excellent patient satisfaction, which may translate into improvement in mood and quality of life.     

Slow-release oral morphine as a maintenance agent in opioid dependence syndrome: an exploratory study from India

Aim: Slow-release oral morphine (SROM) as agonist maintenance agent was introduced recently in India while buprenorphine is available for the past two decades. In this study, the drug use and psychosocial status of opioid-dependent patients who were maintained on buprenorphine and subsequently shifted to SROM were assessed.

Design: This is an observational study.

Procedure: This study was carried out in a community-based drug treatment clinic in New Delhi. Thirty-nine opioid-dependent males maintained on sublingual buprenorphine (for at least 1 month) were included in this study. Due to difficulty in buprenorphine procurement for some period, 34 patients were shifted to SROM after informed consent. Assessments were made prior to the switch-over and after 4 weeks of stabilisation on SROM.

Results: All patients initiated on SROM continued to remain in the treatment during the 4-week period. The low scores on measures of opioid withdrawal symptoms, craving and high scores on quality of life observed while on buprenorphine continued even after 4 weeks of SROM treatment. Patients on SROM reported mild adverse effects.

Conclusion: SROM is as effective as buprenorphine in controlling withdrawal, craving and quality of life on short-term follow-up.     

Use of Methadone to Reverse Opioid Escalation in a Patient With Surgical Pain

ABSTRACT

Acute pain is a prevalent issue for patients recovering from surgical procedures. Methadone has been recognized as a unique option for treatment of surgical pain due to its multiple mechanisms of analgesia and its potential to decrease tolerance to other opioids. Studies of methadone use in postoperative settings are sparse in part due to safety concerns, such as complex pharmacokinetics, risk of respiratory depression, and association with arrhythmias. In this case study of a 70-year-old male with postsurgical abdominal pain, methadone utilization over a period of 9 days resulted in patient-reported analgesia and aided in de-escalating overall opioid use. More studies are needed to develop guidance on how methadone can be used to relieve pain following surgical procedures.     

Transdermal buprenorphine in cancer pain and palliative care

Transdermal buprenorphine has been assessed as a therapy for chronic cancer and non-cancer pain in both clinical and postmarketing surveillance studies. Data from 239 patients who had participated in a follow-up study of up to six years have shown efficacy and safety, and good tolerability over prolonged treatment periods with a marked stability of doses. From the cancer pain population (134 patients), 20% stayed on transdermal buprenorphine until the end of their lives. Postmarketing surveillance study data from 13,179 patients, including 3690 cancer patients assessed during a 10-week observation period, showed that 81% of patients achieved good/very good pain relief with transdermal buprenorphine. Furthermore, 49.6% of patients did not require any analgesic comedication or rescue therapy, a point that is particularly important in the elderly population. Results from the Spanish Pain Society on transdermal buprenorphine in chronic non-cancer, neuropathic and cancer-related pain, and on switching from morphine, also confirmed its beneficial efficacy and safety, and showed that buprenorphine does not antagonize pain relief, or cause withdrawal when combined with full micro-agonists. The effectiveness of buprenorphine is further supported by evidence of its pronounced anti-hyperalgesic effect in a human pain model, which may be a factor in explaining the efficacy of buprenorphine in neuropathic pain. When switching of opioids is indicated to improve pain relief or reduce adverse events, equipotency dosage ratios are important. The equipotency ratio for morphine to buprenorphine, previously established as 75:1, is now being questioned as new data from a retrospective cohort study were published indicating a ratio of 100:1. Moreover, transdermal buprenorphine has superior safety in respect to respiratory depression, immunological and renal effects compared with standard World Health Organization step III opioids, which makes it highly suitable for treating moderate-to-severe pain also in cancer patients, a per se vulnerable patient population requiring a sensible selection of potent analgesics.     

Sublingual buprenorphine versus intravenous or intramuscular morphine in acute pain: A systematic review and meta-analysis of randomized control trials

Intro

Buprenorphine is a potent analgesic agent with several unique and favourable features such as its sublingual formulation. The aim of this study is to compare the effectiveness of sublingual versus intramuscular and intravenous buprenorphine in acute pain.

The effect of buprenorphine on the analgesic and respiratory depressant effects of pethidine: a preliminary study

The effects on respiration and pain perception of giving 0.6 mg buprenorphine alone and of giving the same dose after the administration of pethidine intravenously to achieve a steady-state blood pethidine level (mean blood level 0.29-0.47 microgram/ml) were studied in 3 healthy male volunteers. Depression of ventilation occurred with both pethidine and buprenorphine, and the combination produced greater depression than did either drug alone. Times to onset of, and tolerance to, experimental pain increased with pethidine and buprenorphine, a greater increase occurring when both drugs were combined. There was no evidence that buprenorphine reversed the respiratory depression produced by pethidine, while maintaining analgesia.     

Sublingual buprenorphine for acute renal colic pain management: a double-blind, randomized controlled trial

Background

The aim of this study was to compare the efficacy and safety of sublingual buprenorphine with intravenous morphine sulfate for acute renal colic in the emergency department.

Methods

In this double-dummy, randomized controlled trial, we enrolled patients aged 18 to 55 years who had a clinical diagnosis of acute renal colic. Patients received either 2 mg sublingual buprenorphine with an IV placebo, or 0.1 mg/kg IV morphine sulfate with a sublingual placebo. Subjects graded their pain with a standard 11-point numeric rating scale (NRS) before medication administration and 20 and 40 minutes after that. The need for rescue analgesia and occurrence of side effects were also recorded in the two groups.

Results

Of 69 patients analyzed, 37 had received buprenorphine, and 32 had taken morphine. Baseline characteristics were similar in both groups. NRS pain scores were reduced across time by administration of both buprenorphine (from 9.8 to 5.22 and then 2.30) and morphine (from 9.78 to 4.25 and then 1.8), significantly (P <0.0001). The two regimens did not differ significantly for pain reduction (P?=?0.260). Dizziness was more frequently reported by the buprenorphine group (62.1% versus 37.5%, P <0.05) but other adverse effects observed within 40 minutes were similar in the two groups.

Conclusions

Sublingual buprenorphine (2 mg) is as effective as morphine sulfate (0.1 mg/kg) in acute renal colic pain management.     

A case report of methadone-associated hypoglycemia in an 11-month-old male

Background: Methadone is a synthetic μ-opioid receptor agonist that is used in the management of pain, neonatal abstinence withdrawal syndrome, and opioid dependence. Overdose can cause miosis, respiratory depression, and central nervous system depression. Rarely, hypoglycemia has been reported. We present the case of an 11-month-old male who developed hypoketotic, hyperinsulinemic, hypoglycemia after an acute, unintentional methadone exposure.

Case details: The patient was a previously healthy 11-month-old male who presented in respiratory failure. He was intubated and transferred to a large tertiary care center where his physical exam was notable for miosis. His labs were notable for a blood glucose of 17?mg/dL, an elevated insulin level, and suppressed serum beta-hydroxybutyrate. The patient was given a dextrose bolus with improvement in blood glucose. Administration of IV naloxone improved his miosis and mental status. A quantitative methadone level was sent upon arrival and was 123?ng/mL. Testing for ethanol, salicylates, sulfonylureas, and metabolic causes of hypoglycemia was negative. A fasting study showed euglycemia with suppression of insulin and appropriate ketosis.

Case discussion: We present the case of an 11-month-old male who developed hypoketotic, hyperinsulinemic, hypoglycemia after an acute, unintentional methadone exposure. Alternative explanations for hypoketotic hypoglycemia were rule out. Methadone-induced hypoglycemia has been reported in cancer patients receiving methadone for pain, but a mechanism has not been identified. Based on this case, we believe that the patient’s hypoglycemia was the result of methadone-induced insulin secretion.

Conclusions: This case proposes that hyperinsulinism is the mechanism responsible for methadone-associated hypoglycemia. Methadone exposure should be included in the differential diagnosis of new onset hypoglycemia.     

Opioid dependence treatment, including buprenorphine/naloxone

OBJECTIVE: To review opioid dependence (OD) and its treatment. Pharmacologic treatments, including the use of buprenorphine/naloxone, are presented. Pharmaceutical care functions for outpatient OD treatment are discussed. DATA SOURCES: Primary and review articles were identified by MEDLINE and HEALTHSTAR searches (from 1966 to November 2000) and through secondary sources. Tertiary sources were also reviewed regarding general concepts of OD and its treatment. STUDY SELECTION/DATA EXTRACTION: Relevant articles were reviewed after identification from published abstracts. Articles were selected based on the objectives for this article. Studies of the treatment of OD with buprenorphine were selected based on the topic (pharmacology, pharmacokinetics, adverse reactions) and study design (randomized, controlled clinical trials in patients with OD with active/placebo comparisons and/or comparisons of active OD treatments). Articles regarding pharmacists' activities in the treatment and prevention of OD were reviewed for the pharmaceutical care section. DATA SYNTHESIS: OD is considered a medical disorder with costly adverse health outcomes. Although methadone maintenance treatment (MMT) is cost-effective for OD, only about 12% of individuals with OD receive this treatment. Psychological and pharmacologic modalities are used to treat OD, but patients often relapse. Drug therapy includes alpha 2-agonists for withdrawal symptoms, detoxification regimens with or without opioids, opioid antagonists, and opioid replacement including methadone, levomethadyl acetate, and buprenorphine. The Drug Addiction Treatment Act of 1999 allows for office-based opioid replacement therapies. Sublingual buprenorphine with naloxone can be used in this milieu. Buprenorphine with naloxone is currently under new drug application review with the Food and Drug Administration. Clinical research shows buprenorphine to be equal in effectiveness to methadone, but safer in overdose due to its ceiling effect on respiratory depression. It has lower abuse potential and fewer withdrawal symptoms when discontinued. Naloxone is included to decrease diversion and injection of the tablets. Pharmacists in outpatient settings who are familiar with OD have opportunities to provide pharmaceutical care to patients receiving this treatment. Pharmaceutical care functions for OD include ensuring appropriate drug administration, monitoring adverse effects, alleviating withdrawal symptoms, treating intercurrent illnesses, minimizing diversion, and preventing relapse. CONCLUSIONS: OD is a critical unmet health problem in the US. Buprenorphine combined with naloxone represents an innovative treatment for OD in outpatient settings. This new treatment has advantages over MMT.     

Opioid Rotation from High-Dose Morphine to Transdermal Buprenorphine (Transtec®) in Chronic Pain Patients

Abstract:   Opioid rotation is increasingly becoming an option to improve pain management especially in long-term treatment. Because of insufficient analgesia and intolerable side effects, a total of 42 patients (23 male, 19 female; mean age 64.1 years) suffering from severe musculoskeletal (64%), cancer (21%) or neuropathic (19%) pain were converted from high-dose morphine (120 to >240 mg/day) to transdermal buprenorphine. The dose of buprenorphine necessary for conversion (at least 52.5 µg/h) was titrated individually by the treating physician. No conversion recommendations were given and the treating physician used his or her own judgment for dose adjustment. Pain relief, overall satisfaction and quality of sleep (very good, good, satisfactory, poor, or very poor), and the incidence and severity of adverse drug reactions over a period of at least 10 weeks and up to 1 year was assessed. Following rotation, patients experiencing good/very good pain relief increased from 5% to 76% ( P  < 0.001). Only 5% reported insufficient relief. Relief was achieved with buprenorphine alone in 77.4%, while 17% needed an additional opioid for breakthrough pain. Sleep quality (good/very good) increased from 14% to 74% ( P  < 0.005). Adverse effects were reported in 11.9%, mostly because of local irritation, did not result in termination of therapy. Neither tolerance nor refractory effect following rotation from morphine to buprenorphine was noted. Conversion tables with a fixed conversion ratio are of limited value in patients treated with high-dose morphine.     

Buprenorphine TDS: the clinical development rationale and results

Buprenorphine, a powerful opioid, is newly available for delivery in a transdermal formulation. The transdermal system's matrix patch provides rate-controlled administration of the drug. Three double-blind, placebo-controlled trials were conducted to evaluate efficacy and tolerability of the buprenorphine transdermal system (buprenorphine TDS, Transtec). A total of 445 patients were enrolled in the studies. All suffered from moderate to severe and very severe pain, both cancer- or non-cancer-related. The percentage of responders increased as the rate of buprenorphine delivered by the transdermal system rose, ranging from a 29% (cancer) and 36% (non-cancer) response rate associated with the lowest dose (35 microg/h), to 40% (cancer) and 46% (non-cancer) with the highest dose (70 microg/h). Patients receiving buprenorphine TDS slept longer, uninterrupted by pain, than patients from the placebo group. Systemic adverse effects reported in the drug cohorts included nausea, vomiting and dizziness, and were typical of those reported in other studies of opioids; local adverse events, most commonly erythema and pruritus, were transient and mild to moderate. In an open-label, follow-up trial, in which 239 patients from the original clinical studies participated, 90% of patients reported that their analgesia was satisfactory or even better over a mean duration of 4.7 months; nearly 95% of patients found the patch to be user-friendly. The new buprenorphine TDS appears to be an important new modality for administering analgesia in patients with non-acute pain.     

Current Knowledge of Buprenorphine and Its Unique Pharmacological Profile

Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ‐opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full μ‐opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compound's favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for treating chronic cancer and noncancer pain.