Oral Prolonged‐Release Oxycodone/Naloxone for Managing Pain and Opioid‐Induced Constipation: A Review of the Evidence

Background

Opioids provide effective relief from moderate‐to‐severe pain and should be prescribed as part of a multifaceted approach to pain management when other treatments have failed. Fixed‐dose oxycodone/naloxone prolonged‐release tablets (OXN PR) were designed to address the opioid class effect of opioid‐induced constipation (OIC) by combining the analgesic efficacy of oxycodone with the opioid receptor antagonist, naloxone, which has negligible systemic availability when administered orally. This formulation has abuse‐deterrent properties, since systemic exposure to naloxone by parenteral administration would antagonize the euphoric effects of oxycodone.

Methods

A literature search was conducted to assess the evidence base for OXN PR to treat moderate‐to‐severe pain and its impact on bowel function, based on published clinical trials and observational studies.

Results

Extensive data demonstrate that OXN PR provides effective analgesia and clinically relevant improvements in bowel function in patients with OIC and moderate‐to‐severe cancer‐related pain and noncancer pain types such as low back pain, neuropathic pain, and musculoskeletal pain. OXN PR has also been found to improve bowel function in patients with OIC refractory to multiple types of laxatives, and improve Parkinson's disease–related pain. No unanticipated safety concerns have been reported in elderly patients.

Conclusions

Evidence from clinical trials and observational studies confirms that for selected patients OXN PR significantly improves moderate‐to‐severe chronic pain and provides relief from OIC. Treatment should be tailored to individual patients to establish the lowest effective dose. An absence of analgesic ceiling effect was seen across the clinically relevant dose range investigated (≤ 160/80 mg/day).     

Opioid‐Free Perioperative Analgesia for Hemicolectomy in a Patient With Opioid‐Induced Delirium: A Case Report and Review of the Analgesic Efficacy of the Alpha‐2 Agonist Agents

Abstract: Surgical pain in patients with documented opioid‐induced delirium can be difficult to treat. We present a case of a patient undergoing laparoscopic hemicolectomy effectively treated with an opioid‐free, alpha‐2 adrenoreceptor agonist analgesic regimen. Case report: A 21‐year‐old woman with persistent abdominal pain presented to the operating room for laparoscopic hemicolectomy for redundant right colon. Her medical history included a recently diagnosed postoperative opioid‐induced delirium. Epidural infusion with local anesthetic offered partial pain relief with sensory levels of T9‐L2. With the addition of dexmedetomidine infusion in the immediate postoperative period, the patient was comfortable with pain scores of 1 to 2/10 on Numerical Rating Scale (NRS). On postoperative day 1, the infusion was discontinued and the clonidine, 12 μg/hours was added to the epidural bupivacaine. With increased sedation 48 hours later, neuraxial clonidine was discontinued in favor to transdermal clonidine 0.1 mg/week, which was maintained until hospital discharge. Pain scores were maintained at 2 to 3/10 on NRS for the next 3 days when increased abdominal distention because of abscess formation rendered a new surgical intervention. The analgesia for the exploratory laparoscopy was maintained using epidural clonidine and bupivacaine infusion as well as intravenous dexmedetomidine, which were maintained another 2 days. Pain scores remained minimal until discharged home 3 day later. Discussion: Nonopioid analgesic regimens are beneficial in patients at risk of postoperative cognitive dysfunction attributable to opioids. Successful postoperative analgesia was achieved in our patient by alternating various routes of administration of alpha‐2 adrenoreceptor agonists.     

Treatment of Chronic Pain by Long‐Acting Opioids and the Effects on Sleep

Chronic pain affects a substantial part of the population, and conveys a huge economic cost to society. Owing to its prevalence and adverse impact, it is of particular interest to clinicians, patients, and the pharmaceutical industry. Conversely, the effects of pain on sleep, sleep on pain, and opioid analgesics on sleep represent a large gap in our understanding, even though pain and sleep are closely linked, inter‐related conditions. Chronic pain is often treated by opioid analgesics, which are often thought to promote restful sleep. Indeed it may be assumed that by relieving pain, sleep quality will improve concomitantly. In fact, the reality is much more complicated. The effects of opioids vary according to their formulation and duration of action, and have diverse effects on sleep processes. Despite the prevalence of this problem, there is a surprising paucity of data on the effects of opioids on sleep. This review attempts to summarize the links between pain and sleep, and to look at the studies with opioid analgesics, particularly those with extended‐release formulations, that have investigated the effects of opioid analgesics on sleep.     

Postoperative Pain Management in Spanish Hospitals: A Cohort Study Using the PAIN-OUT Registry

Pain after surgery remains a problem worldwide, although there are no published data on postoperative outcomes in Spain. We evaluated 2,922 patients on the first day after surgery in 13 tertiary care Spanish hospitals, using the PAIN-OUT questionnaire. The aims were to: assess postoperative outcomes and anesthetic/analgesic management in Orthopedics (ORT) and General Surgery (GEN) patients; explore the influence of the analgesic therapy on outcomes and opioid requirements; evaluate and compare outcomes and analgesic management according to surgical procedure. Mean worst pain and percentage of patients in severe pain were 5.6 (on a numeric rating scale of 0–10) and 39.4%, respectively, slightly lower than those reported in Western countries (range, 5.0–8.4 and 33–55%). Patients’ pain assessment (83.1%) and information were high (63.3%), but participation in decision-making (4.8) was lower than in the United States (7.0) and Europe (Germany, France, Norway, and Denmark; mean, 5.9). Patients after orthopedic surgery had the worst outcomes. General anesthesia was more frequent in GEN patients, whereas regional (central and peripheral) was more frequent in ORT surgery patients. Mean opioid consumption (20.2 mg per patient per 24 hours, oral morphine equivalents), was lower than reported and decreased >50% after regional analgesia. Intravenous morphine patient-controlled analgesia was seldom used (6.2%). Acute opioid treatments were associated with worsened outcomes whereas multimodal analgesia (mainly antipyretic analgesics–nonsteroidal anti-inflammatory drugs–opioids) were associated with improved results. Epidurals in abdominal surgery (16.7%) were also associated with better outcomes. Presurgical chronic pain (>7) and/or chronic opioid consumption, were associated with worsened pain outcomes; the latter with a 50% increase in postoperative opioid requirements. Tibia/fibula and foot surgeries (ORT), and gastric, small intestine, and anterior abdominal wall procedures (GEN) were the most painful. Rigorous control of chronic pain before surgery, and combining opioids with adjuvants and other analgesics perioperatively, might improve postoperative outcomes.

Coadministration of an Opioid Agonist and Antagonist for Pain Control

Abstract: The increased use of opioids in the treatment of chronic pain encourages the search for drugs with low abuse and tolerance potential but with potent analgesic activity. Opioid agonist‐antagonists and partial agonists have less abuse potential than do mu opioid receptor agonists such as morphine, and have been used for many years for their analgesic affects. Recently they have been approved for treatment of opioid addiction. As a guard against abuse, an opioid antagonist, such as naloxone, is added to some opioid formulations. Doctors are often hesitant to prescribe agonist‐antagonists and partial agonists to opioid‐tolerant patients, fearing that these drugs may precipitate withdrawal. Can drugs being used safely for addiction treatment also safely replace opioid agonists to provide analgesia in chronic pain patients who are opioid‐tolerant?     

Are Psychoactive Substance (Opioid)‐Dependent Chronic Pain Patients Hyperalgesic?

Objectives: One indirect line of evidence for opioid‐induced hyperalgesia (OIH) in humans is decreased pain thresholds (PTREs) and tolerances (PTOLs) in opioid addicts on opioids. There are a number of such studies in opioid maintained addicts, but no such studies in chronic pain patients (CPPs) with current opioid addiction. The objective of this study was to determine if this group demonstrates hyperalgesia. Methods: CPPs were subdivided into those with psychoactive substance (opioid dependence) (PSOD) (n = 38) (addicted) and those taking opioids but without PSOD (n = 198) (not addicted). A group of opioid‐free non‐CPPs served as a control group (n = 36). PTREs/PTOLs were determined in each group by pressure pain stimulation in both the right and left index fingers. PTREs/PTOLs were compared by analysis of variance among the three groups controlling for sex/age and by analysis of covariance between the PSOD CPPs and non‐PSOD CPPs controlling for duration of pain and visual analog scale pain level over the last 24 hours. Results: The PSOD and non‐PSOD CPPs had significantly lower PTREs and PTOLs vs. the control group, ie, were hyperalgesic. However, they were not significantly different from each other. Conclusions: This study contributes to the human OIH literature. However, because of the potential confounders in this study, the issue of OIH in humans remains unresolved.     

The Role of Opioids in Cancer Pain Management

Abstract:   Opioids remain an important cornerstone in the treatment of cancer pain. Effective analgesia is obtained in the majority of cancer pain patients with the application of fairly straightforward algorithms using opioids as the main therapy. Many rational treatment algorithms exist. In this tutorial we will describe the role of opioids in the treatment of cancer pain, including a brief overview of cancer pain syndromes, essential aspects of opioid therapy, opioid pharmacology, opioid rotation, properties of the individual opioids, and management of common side effects of opioids.     

End‐of‐Dose Pain in Chronic Pain: Does it Vary with the Use of Different Long‐Acting Opioids?

A large percentage of patients with chronic pain on around‐the‐clock (ATC) opioids may experience increased pain occurring at the end of a scheduled dose, also known as end‐of‐dose pain. Despite the significant prevalence and impact of end‐of‐dose pain in patients using extended‐release (ER) opioids, there are no detailed analyses examining how the frequency of end‐of‐dose pain is linked to the formulations of long‐acting opioids. Consequently, we performed a systematic review to evaluate how many published studies on patients with chronic cancer or noncancer pain identified end‐of‐dose pain. As only a few studies mentioned end‐of‐dose pain explicitly, we used breakthrough pain (BTP) as a surrogate parameter. We determined if any opioid formulation had a greater association with the frequency of BTP, the use of rescue medication for BTP, and the frequency of end‐of‐dose pain. Of the 39 studies entered in the final analysis, 14 studies across different formulations showed that ER opioids were effective in the prevention of BTP. The opioids most frequently studied were hydromorphone (26%), followed by morphine (23%), and transdermal buprenorphine (23%). Only 5% of the studies used immediate‐release preparations. Overall, most studies showed that patients using ER preparations experienced fewer episodes of BTP compared with patients on placebo or an active comparator. This could reflect the favorable duration of action of these opioids compared with short‐acting formulations. Future studies should examine the incidence of end‐of‐dose pain and use of rescue medicine in a longitudinal manner in patients with chronic pain taking short‐ vs. long‐acting ATC opioids.     

Improved Cancer Pain Treatment Using Combined Fentanyl-TTS and Tramadol

? Abstract: The aim of the study was to facilitate dose escalation of strong opioids. In this randomized open‐label study the influence of tramadol on dose adjustment of transdermal fentanyl in advanced cancer pain control was prospectively evaluated. Seventy patients affected by intractable cancer disease with visual analog scale (VAS) score >3 were enrolled. Thirty‐five patients were treated conventionally with increasing transdermal fentanyl dosage as required (group F) and 35 patients received oral tramadol added to their transdermal fentanyl before each increment of the transdermal opioid dosage (group T). Pain control was equally satisfactory in the two groups. VAS scores at baseline (T: 4.36 ± 1.53; F: 4.51 ± 1.36; n.s.) and at the end of the study (T: 1.8 ± 1.6; F: 1.6 ± 1.5; n.s.) did not differ. However, in the tramadol group this level of pain control was achieved with much slower dose escalation of fentanyl. The mean application time of the fentanyl‐Transdermal Therapeutic System patch for each dosage (25, 50, 75 μg/hour) was significantly greater in patients receiving tramadol. No patient in group T escalated to the 100 μg/hour patch, while in 12 patients of group F the 100 μg/hour patch was applied after a 75 μg/hour patch mean application period of 18.6 ± 4.7 days. The number of fentanyl‐TTS dosage changes was significantly lower in group T (1.2 ± 0.4 vs. 2.3 ± 0.5; P < 0.05). The mean total duration of treatment in group T, was 37.1 ± 11.6 days. The amount of fentanyl used at study end was 56.6 ± 11.2 μg/hour plus 141.1 ± 151.9 mg tramadol per day (median: 200 mg/day) in group T patients compared with 84.1 ± 12.2 μg/hour in group F patients (P < 0.05). The combination of a strong opioid with a weak opioid to treat severe cancer pain allowed a more gradual increase of analgesic delivery than was possible using fentanyl‐TTS alone, minimizing periods of under‐ and overdosing. In addition, it considerably slowed the pace of fentanyl dose escalation. In conclusion, this TTS fentanyl‐tramadol analgesic protocol provides a useful alternative to the usual treatment of cancer pain with fentanyl‐TTS alone, especially in case of quick progression of disease and pain. ?     

Preoperative Gabapentin for Acute Post‐thoracotomy Analgesia: A Randomized,Double‐Blinded,Active Placebo‐Controlled Study

Background: The role of preoperative gabapentin in postoperative pain management is not clear, particularly in patients receiving regional blockade. Patients undergoing thoracotomy benefit from epidural analgesia but still may experience significant postoperative pain. We examined the effect of preoperative gabapentin in thoracotomy patients. Methods: Adults undergoing elective thoracotomy were enrolled in this prospective, randomized, double‐blinded, placebo‐controlled study, and randomly assigned to receive 600 mg gabapentin or active placebo (12.5 mg diphenhydramine) orally within 2 hours preoperatively. Standardized management included thoracic epidural infusion, intravenous patient‐controlled opioid analgesia, acetaminophen and ketorolac. Pain scores, opioid use and side effects were recorded for 48 hours. Pain was also assessed at 3 months. Results: One hundred twenty patients (63 placebo and 57 gabapentin) were studied. Pain scores did not significantly differ at any time point (P = 0.53). Parenteral and oral opioid consumption was not significantly different between groups on postoperative day 1 or 2 (P > 0.05 in both cases). The frequency of side effects such as nausea and vomiting or respiratory depression was not significantly different between groups, but gabapentin was associated with decreased frequency of pruritus requiring nalbuphine (14% gabapentin vs. 43% control group, P < 0.001). The frequency of patients experiencing pain at 3 months post‐thoracotomy was also comparable between groups (70% gabapentin vs. 66% placebo group, P = 0.72). Conclusions: A single preoperative oral dose of gabapentin (600 mg) did not reduce pain scores or opioid consumption following elective thoracotomy, and did not confer any analgesic benefit in the setting of effective multimodal analgesia that included thoracic epidural infusion.     

Current Considerations for the Treatment of Severe Chronic Pain: The Potential for Tapentadol

Abstract Studies suggest that around 20% of adults in Europe experience chronic pain, which not only has a considerable impact on their quality of life but also imposes a substantial economic burden on society. More than one‐third of these people feel that their pain is inadequately managed. A range of analgesic drugs is currently available, but recent guidelines recommend that NSAIDs and COX‐2 inhibitors should be prescribed cautiously. Although the short‐term efficacy of opioids is good, adverse events are common and doses are frequently limited by tolerability problems. There is a perceived need for improved pharmacological treatment options. Currently, many treatment decisions are based solely on pain intensity. However, chronic pain is multifactorial and this apaproach ignores the fact that different causative mechanisms may be involved. The presence of more than one causative mechanism means that chronic pain can seldom be controlled by a single agent. Therefore, combining drugs with different analgesic actions increases the probability of interrupting the pain signal, but is often associated with an increased risk of drug/drug interactions, low compliance and increased side effects. Tapentadol combines μ‐opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule, with both mechanisms contributing to its analgesic effects. Preclinical testing has shown that μ‐opioid agonism is primarily responsible for analgesia in acute pain, whereas noradrenaline reuptake inhibition is more important in chronic pain. In clinical trials in patients with chronic pain, the efficacy of tapentadol was similar to that of oxycodone, but it produced significantly fewer gastrointestinal side‐effects and treatment discontinuations. Pain relief remained stable throughout a 1‐year safety study. Thus, tapentadol could possibly overcome some of the limitations of currently available analgesics for the treatment of chronic pain.     

The Role of Urine Drug Testing for Patients on Opioid Therapy

Opioid analgesics must be prescribed with discernment and their appropriate use should be periodically assessed. Urine drug testing, although not designed specifically for this role, is a widely available and familiar method for monitoring opioid use in chronic pain patients. Urine drug testing can help track patient compliance and expose possible drug misuse and abuse. We sought to evaluate current attitudes and practices regarding the use of urine drug testing among chronic pain patients taking opioids. To the best of our knowledge, this is one of the first such attempts in the literature to examine and document the practice patterns of urine drug testing in this context. A total of 99 attendees at the American Congress of Pain Medicine were surveyed in 2008 about their urine testing practices for patients on opioid therapy. Surprisingly, more urine testing was motivated by a desire to detect undisclosed substances than to evaluate appropriate opioid use. Some respondents never urine‐tested their opioid patients, and about two‐thirds of respondents had no formal training in urine testing of patients on opioid therapy. The literature does not thoroughly address the role of urine drug testing in this patient population. Most respondents did random rather than scheduled testing; few had any urine testing protocol. The study found motivations for urine testing and testing practices varied widely, and urine testing, despite its clinical utility, is not used consistently.     

Treatment Considerations for Cancer Pain: A Global Perspective

Cancer pain is prevalent, undertreated, and feared by patients with cancer. In April 2013, a panel of pain experts convened in Singapore to address the treatment of cancer pain. They discussed the various types of cancer pain, including breakthrough pain, which is sometimes clinically confused with analgesic gaps. Reasons for undertreating cancer pain include attitudes of patients, clinicians, and factors associated with healthcare systems. The consequences of not treating cancer pain may include reduced quality of life for patients with cancer (who now live longer than ever), functional decline, and increased psychological stress. Early analgesic intervention for cancer pain may reduce the risk of central sensitization and chronification of pain. To manage pain in oncology patients, clinicians should assess pain during regular follow‐up visits using validated pain measurement tools and follow prescribing guidelines, if necessary referring patients with cancer to pain specialists. Many patients with cancer require opioids for pain relief. Pain associated with cancer may also relate to cancer treatments, such as chemotherapy‐induced peripheral neuropathy. Many patients with cancer are what might be considered “special populations,” in that they may be elderly, frail, comorbid, or have end‐stage organ failure. Specific pain therapy guidelines for those populations are reviewed. Patients with cancer with a history of or active substance abuse disorder deserve pain control but may require close medical supervision. While much “treatment inertia” exists in cancer pain control, cancer pain can be safely and effectively managed and should be carried out to alleviate suffering and improve outcomes.     

Long‐term Safety and Tolerability of Tapentadol Extended Release for the Management of Chronic Low Back Pain or Osteoarthritis Pain

Background: Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action: µ‐opioid receptor agonism and norepinephrine reuptake inhibition. This randomized, open‐label phase 3 study (ClinicalTrials.gov Identifier: NCT00361504) assessed the long‐term safety and tolerability of tapentadol extended release (ER) in patients with chronic knee or hip osteoarthritis pain or low back pain. Methods: Patients were randomized 4:1 to receive controlled, adjustable, oral, twice‐daily doses of tapentadol ER (100 to 250 mg) or oxycodone HCl controlled release (CR; 20 to 50 mg) for up to 1 year. Efficacy evaluations included assessments at each study visit of average pain intensity (11‐point numerical rating scale) over the preceding 24 hours. Treatment‐emergent adverse events (TEAEs) and discontinuations were monitored throughout the study. Results: A total of 1,117 patients received at least 1 dose of study drug. Mean (standard error) pain intensity scores in the tapentadol ER and oxycodone CR groups, respectively, were 7.6 (0.05) and 7.6 (0.11) at baseline and decreased to 4.4 (0.09) and 4.5 (0.17) at endpoint. The overall incidence of TEAEs was 85.7% in the tapentadol ER group and 90.6% in the oxycodone CR group. In the tapentadol ER and oxycodone CR groups, respectively, TEAEs led to discontinuation in 22.1% and 36.8% of patients; gastrointestinal TEAEs led to discontinuation in 8.6% and 21.5% of patients. Conclusion: Tapentadol ER (100 to 250 mg bid) was associated with better gastrointestinal tolerability than oxycodone HCl CR (20 to 50 mg bid) and provided sustainable relief of moderate to severe chronic knee or hip osteoarthritis or low back pain for up to 1 year.