Bruce Nicholson

Responsible Prescribing of Opioids for the Management of Chronic Pain

The management of patients with chronic pain is a common clinical challenge. Indeed, chronic pain is often inadequately controlled in patients with cancer and in those with non-cancer chronic pain. Because of the complex nature of chronic pain, successful long-term treatment is more difficult than for acute pain. Most often acute pain is nociceptive, whereas chronic pain can be nociceptive (i.e., in response to noxious stimuli), neuropathic (i.e., initiated by a primary lesion or dysfunction in the nervous system) or mixed in origin.Opioids are the current standard of care for the treatment of moderate or severe nociceptive pain. Opioids mediate their actions by binding and activating receptors both in the peripheral nervous system and those that are found in inhibitory pain circuits that descend from the midbrain to the spinal cord dorsal horn. Opioid agonists exert a number of physiological responses including analgesia, which increases with increasing doses.The use of opioids to manage pain in patients with cancer is well accepted. The WHO step-wise algorithm for analgesic therapy based on pain severity reserves the use of opioid therapy for moderate and severe pain. The WHO algorithm has proven to be highly effective for the management of cancer pain. However, the use of opioids to treat patients with chronic non-cancer pain is controversial because of concerns about efficacy and safety, and the possibility of addiction or abuse. The results of clinical surveys and retrospective case series involving patients with non-cancer chronic pain have been inconsistent in regard to resolving these controversial issues.The oral route of drug administration is most appropriate for patients receiving opioids; although rectal, transdermal and parenteral routes of administration are used in specific situations. For continuous chronic pain, opioids should be administered around-the-clock and several long-acting formulations are available that require administration only once or twice daily. Opioid doses should be titrated according to agent-specific schedules to maximise pain relief and maintain tolerability. Adverse effects include constipation, nausea and vomiting, sedation, cognitive impairment and respiratory depression. Tolerance to the analgesic and adverse effects as well as physical dependence, which causes withdrawal symptoms upon discontinuance, may occur with opioid use. Estimates of addiction rates among patients with chronic non-cancer pain range from 3.2 to 18.9%.Successful pain treatment and symptom management is an attainable goal for the majority of patients with chronic pain. Further controlled clinical trials are needed to define the role of opioid therapy in chronic non-cancer pain, and to establish criteria for patient selection and specific treatment algorithms.

Lidocaine patch treatment in patients with low back pain : Results of an open-label, nonrandomized pilot study

This prospective, 6-week, multicenter, open-label, nonrandomized pilot study was designed to assess the effectiveness and safety of a lidocaine patch 5% in patients with low back pain (LBP). Patients with moderate to severe LBP, defined as acute/subacute (<3 months, n = 21), short-term chronic (3-12 months, n = 33), or long-term chronic (>12 months, n = 77), were recruited from 5 clinics; participants applied ≤4 patches (560 cm2 total) once daily to area of maximal LBP as add-on treatment through week 2, with the option to taper concomitant analgesics during weeks 3-6. Scores on Brief Pain Inventory (BPI) were obtained at weeks 2 and 6. Safety analyses included reports of adverse events (AEs) and skin sensitivity to pinprick/light touch. Significant improvements in average daily pain intensity on the BPI were noted at weeks 2 and 6 (P ≤ 0.001). Significant improvements in pain interference with quality of life (QOL) were noted for all BPI measures of QOL at weeks 2 and 6 for the acute/subacute (P ≤ 0.007) and long-term chronic LBP groups (P < 0.0001) and for 5 of 7 BPI measures for the short-term chronic LBP group (P ≤ 0.042). Fifty-eight percent of patients reported being “satisfied” or “very satisfied” with treatment. The lidocaine patch was well tolerated. Most common AEs were dizziness and rash (n = 5, 3.8%), and most AEs (80%) were mild to moderate in intensity. Significant improvement in pain intensity and QOL in this cohort of LBP patients was noted during treatment with the lidocaine patch 5%. Controlled clinical trials are warranted.

Randomized trial comparing polymer-coated extended-release morphine sulfate to controlled-release oxycodone HCl in moderate to severe nonmalignant pain

ABSTRACT Objective: To assess the long-term efficacy, tolerability and safety of polymer-coated extended- release morphine sulfate (P-ERMS) (KADIAN*) compared with controlled-release oxycodone HCl (CRO) (OxyContin†) in treating chronic, nonmalignant, moderate to severe pain in a community- based outpatient population. * KADIAN is a licensed trademark of Alpharma Branded Products Division Inc., Piscataway, NJ, USA † OxyContin is a registered trademark of Purdue Pharma L.P., Stamford, CT, NJ, USA Design: Phase IV, prospective, randomized, open-label. Participants: Adults (N = 112) with chronic, nonmalignant, moderate to severe pain with visual numeric scale (VNS) scores ≥ 4 (0 = no pain; 10 = worst pain). Interventions: Patients were randomized to receive either P-ERMS once-daily (QD) dosing or CRO twice-daily (BID) dosing for a 24‐week treatment period. Upward titration of dose and switching P-ERMS to BID or CRO to thrice-daily (TID) dosing was allowed Weeks 2–24. Main outcome measures: Quality of life (Physical [PCS] and Mental [MCS] Component Summary scores of the SF-36v2 Health Survey), pain and sleep scores (0–10), and patient and clinician assessments of current therapy (–4 to +4). Results: Patients in both treatment groups experienced significant improvements in PCS scores (P-ERMS, +2.6; CRO, +3.1; p < 0.05 vs. baseline); patients taking CRO also demonstrated improvements in MCS scores (+4.7, p < 0.05 vs. baseline). Both groups attained significant reductions from baseline to 24 weeks in pain (P-ERMS, –2.0; CRO, –1.4; p ≤ 0.001 vs. baseline); the reduction with P-ERMS was clinically meaningful (as defined by at least a 2‐point reduction in VNS score). Patients attained significant improvement in sleep scores (P-ERMS, –2.6; CRO, –1.6; p < 0.001 vs. baseline; p < 0.05, P-ERMS vs. CRO). At Week 24, both groups indicated significantly increased patient (P-ERMS, +2.6; CRO, +1.7; p < 0.001 vs. baseline) and clinician (P-ERMS, +4.0; CRO, +3.1; p < 0.001 vs. baseline) global assessments of therapy. After 24 weeks, all patients on P-ERMS were dosing within the FDA-approved frequencies (65% QD, 35% BID); 56% of patients on CRO dosed BID, but 38% dosed TID and 6% dosed four times daily (QID). Most common adverse events were constipation, nausea, and somnolence, with no significant difference between treatment groups. Conclusions: P-ERMS and CRO both relieved chronic nonmalignant pain in this community-based population; however, patients taking P-ERMS dosed in accordance with FDA-approved frequencies (QD/BID); 44% of those taking CRO dosed more frequently (TID/QID).

Treatment of chronic moderate-to-severe non-malignant pain with polymer-coated extended-release morphine sulfate capsules.

ABSTRACT Objective: To demonstrate the efficacy and tolerability of polymer-coated extended-release morphine sulfate (P-ERMS) (KADIAN*) for the treatment of chronic, moderate-to-severe, non-malignant pain in a community-based outpatient population not satisfactorily relieved with their current therapies. * KADIAN is a registered trademark of Alpharma Branded Products Division Inc., Piscataway, NJ Design: Phase IV, prospective, randomized, open-label, blinded endpoint. Participants: Adults (N = 1428) with chronic, moderate-to-severe, non-malignant pain with visual numeric scale scores ≥ 4 (0 = no pain; 10 = worst pain). Interventions: Patients were randomized to P‐ERMS once daily in am or pm for a 4‐week treatment period. Dose increases were allowed; however, switching to twice-daily dosing was reserved until week 2. Main outcome measures: Improvement from baseline in pain and sleep scales (0–10) (after weeks 2 and 4), quality of life (physical and mental component summary scores of the SF-36v2 Health Survey) (week 4), and patient (weeks 2 and 4) and clinician (week 4) assessments of current therapy (–4 to +4). Patient satisfaction was assessed again 1 month after the study. Results: Approximately 70% of patients completed the study, with 2.4% (n = 34) discontinuing due to lack of efficacy, and 9.6% (n = 136) discontinuing due to an adverse event. Improvements were seen in pain and sleep scores, physical and mental component scores of the SF-36v2, and patient and clinician global assessment scores ( p < 0.0001, all assessments). Patients attained similar results regardless of am vs. pm dosing. More than half (55.4%) of patients were maintained on once-daily therapy, with the remainder on a twice-daily regimen, in accordance with the prescribing information. Most adverse events (71.6%) were mild to moderate in severity, the most common being constipation (11.6%) and nausea (9.2%). One‐month follow-up indicated continued satisfaction with P‐ERMS vs. previous medication ( p < 0.0001). Conclusions: P‐ERMS was efficacious and well tolerated in patients with chronic, moderate-to-severe, non-malignant pain when used once or twice daily.

Primary care considerations of the pharmacokinetics and clinical use of extended-release opioids in treating patients with chronic noncancer pain.

Abstract Extended–release (ER) opioid analgesics are associated with prolonged analgesia and greater stability in pain relief compared with immediate–release formulations. Due to the pharmacokinetic (PK) characteristics of ER opioids and additional clinical advantages, the use of ER opioids for patients with moderate–to–severe chronic noncancer pain has increased. Primary care physicians are the major prescribers of opioids and require an in–depth understanding of the risks and benefits of opioid treatment in pain management. With appropriate knowledge of PK profiles and clinical outcomes of commonly prescribed ER opioids, primary care physicians can safely and effectively manage this patient population. In addition, the development of ER opioids with abuse–deterrent features marks an important milestone in potentially reducing abuse and may be factored into the clinical decision–making process. This article provides a comprehensive review of the PK and clinical effects of ER opioids and discusses novel ER opioid formulations that may limit abuse potential.

Effectiveness of polymer-coated extended-release morphine sulfate capsules in older patients with persistent moderate-to-severe pain: A subgroup analysis of a large, open-label, community-based trial

UNLABELLED Abstract. BACKGROUND Opioid analgesics may offer benefits over nonopioids in some older patients, especially those with moderate-to-severe pain. Polymer-coated extended-release morphine sulfate (P-ERMS) has been found to be efficacious and well tolerated in patients with chronic, moderate-to-severe, nonmalignant pain when used QD or BID. OBJECTIVE The purpose of this analysis was to determine the effectiveness of P-ERMS in older patients (aged >65 years) with persistent, moderate-to-severe, inadequately controlled, nonmalignant pain. METHODS This was a subgroup analysis of the older population from an openlabel trial in community-based pain clinics in which patients underwent treatment with P-ERMS for persistent, moderate-to-severe, inadequately controlled, nonmalignant pain (≥4 on a scale of 0-10). Patients received P-ERMS at a dose determined by the investigator based on their previous analgesic regimen, QD (morning or evening) for a 4-week treatment period. Dose increases were permitted after weeks 1 and 2; switching to BID was allowed after week 2, if needed. Measurements included changes in pain and sleep scores (0-10 scale), quality of life (QOL) scores (physical and mental component summaries [PCS and MCS, respectively] of the 36-Item Short-Form Health Survey instrument), and patient and clinician assessments of current treatment based on a 9-point scale ranging from -4 to +4. RESULTS One hundred forty-eight older patients (mean [SD]age, 73.4 [5.5] years) began treatment with P-ERMS; 86 (58.1%) of those patients completed the study. Pain and sleep scores significantly improved (decreased) from baseline to week 4 (7.4 vs 5.0 and 5.0 vs 3.2, respectively; both, P < 0.001). PCS and MCS scores significantly improved (increased) from baseline (27.7 vs 31.6 and 37.6 vs 40.8, respectively; both, P < 0.05), as did patient and clinician global assessments (-1.2 vs 1.1 and -1.5 vs 1.4; both, P < 0.001). Results found in these older patients were similar to those observed in the younger patients (aged ≤65 years). A majority (71.4%) of the older patients remained on QD administration and took significantly lower mean daily doses than younger patients (77.0 vs 105.2 mg/d, respectively; P = 0.001). The dropout rate for the subgroup was 41.1%, which was similar to that reported in previous studies in mixed-age populations taking other extended-release morphine formulations. Of the patients who discontinued (n = 60), adverse events (AEs) were the most prevalent reason (n = 29). The most common treatment-related AEs were constipation (19.6%) and nausea (9.5%). CONCLUSIONS This subgroup analysis of a previously published study revealed that the older patients in that study who were receiving P-ERMS for persistent, moderate-to-severe, inadequately controlled, nonmalignant pain who completed the study attained significant improvements in pain, sleep, and QOL scores compared with baseline. Patient and clinician satisfaction with treatment increased significantly from baseline to study end. Older patients utilized significantly lower mean daily doses than younger patients (P < 0.001), and >70% remained on a QD administration regimen for the duration of the study.

Economic and clinical burden of opioid-induced nausea and vomiting

ABSTRACT Opioids are the standard of care for treating moderate-to-severe pain; however, their efficacy can be limited by adverse events (AEs), including nausea and vomiting. Opioid-induced nausea and vomiting (OINV) is an inherent adverse effect of opioid treatment, exerting effects centrally and peripherally. Opioid-related AEs can impact treatment adherence and discontinuation, which can result in inadequate pain management. OINV may persist long-term, negatively affecting patient functional outcomes, physical and mental health, patient satisfaction, and overall costs of treatment. Multiple factors may contribute to OINV, including activation of opioid receptors in the chemoreceptor trigger zone, vestibular apparatus, and gastrointestinal tract. Prophylactic or early treatment with antiemetics may be appropriate for patients who are at high risk for OINV.

The payer side: patient outcomes and cost

Payers and clinicians share a commitment to successful clinical outcomes in patients with acute or chronic pain. However, there are several issues that concern payers and managed care plans, including the cost of therapy and the cost of treating side effects. This article reviews the economic implications of pain management and the need to provide care in a clinically and economically responsible way. The article also addresses the value of medications to patients, the need for more judicious use of very expensive medications, and the use of evidence-based treatment guidelines. Am J Ther. 2008;15:S20-S23.

Anticonvulsant Medications for Treatment of Neuropathic and “Functional” Pain

The broad definition of neuropathic pain as articulated by the International Association of Pain, “pain initiated or caused by a primary lesion or dysfunction of the nervous system,” unfortunately has done little to guide the clinician when attempting to develop an effective treatment plan that may include an anticonvulsant medication. Current guidelines and indications for use of anticonvulsant therapy primarily utilize a lesion-based approach when recommending treatment for patients suffering from neuropathic pain. However, recent work would suggest that selection of patients based on sensory symptoms and signs rather than strictly by disease etiology has potential benefits in identifying successful therapeutic outcomes.

Comment and Reply on:Randomized trial comparing polymer-coated extended-release morphine sulfate to controlled-release oxycodone HCl in moderate to severe nonmalignant pain

We are writing in response to the study entitled ‘Randomized trial comparing polymer-coated extended-release morphine sulfate to controlled-release oxycodone HCl in moderate to severe nonmalignant pain’, published in the August 2006 issue of Current Medical Research and Opinion by Nicholson et al.. We agree with the authors that for patients with chronic pain, opioids should be administered around-theclock to achieve continuous pain relief, and modifiedrelease dosage forms of morphine and oxycodone provide additional options to appropriate patients with moderate to severe chronic pain. The stated purpose of this study was ‘to compare the efficacy, tolerability and safety’ of polymer-coated extended-release morphine sulfate (P-ERMS; Kadian*) to that of controlledrelease oxycodone HCl (CRO; OxyContin†) ‘in the long-term treatment of chronic, moderate to severe, nonmalignant pain in a community-based outpatient population’. While we commend the stated aim of the study, the method of the study and conclusions lead to concerning and misleading inferences regarding the dosing and administration of CRO Tablets. First, we would like to address this statement in the ‘Introduction’ section: ‘Clinicians have reported that effective pain relief with CRO may require dosing three times daily (TID) or even four times daily (QID) ’. The three references cited in support of this statement are not well-controlled clinical studies evaluating the safety and efficacy of dosing CRO more frequently than q12h, but rather are two retrospective chart reviews and a patient-reported utilization survey. These reviews and survey did not evaluate patients’ pain control or tolerability of the medication with more frequent dosing schedules and therefore, from a safety and efficacy standpoint, are not adequate references to support CRO dosing at less than q12h intervals. Next, we would like to comment on the titration protocol presented in Figure 1 of the ‘Study design/ methodology’ section. We are perplexed with the rationale for the titration design where ‘after Weeks 2, 4, 8 and 12 clinicians were allowed to up-titrate the dose of study medication (if not increased during the previous visits) or to switch to BID dosing of P-ERMS or TID dosing of CRO (if the dose was increased at the previous visit). After Week 12, if necessary, the clinician could adjust the patient’s dosing as clinically indicated during the interim.’ While it is not clear what is meant by ‘the clinician could adjust the patient’s dosing as clinically indicated’, the titration scheme to increase the CRO dosing frequency is not consistent with the recommended dosing for CRO. As stated in the prescribing information for CRO, it is most appropriate to increase the q12h dose, not the dosing frequency. There are no well-controlled clinical studies on dosing intervals shorter than q12h. The efficacy and safety of CRO q12h has been well substantiated by numerous controlled clinical trials in various chronic pain states.