Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial.

UNLABELLED: Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge. Nabiximols (Nabiximols is the U.S. Adopted Name [USAN] for Sativex [GW Pharma Ltd, Wiltshire, U.K.], which does not yet have an INN), a novel cannabinoid formulation, is undergoing investigation as add-on therapy for this population. In a randomized, double-blind, placebo-controlled, graded-dose study, patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose (1-4 sprays/day), medium dose (6-10 sprays/day), or high dose (11-16 sprays/day). Average pain, worst pain and sleep disruption were measured daily during 5 weeks of treatment; other questionnaires measured quality of life and mood. A total of 360 patients were randomized; 263 completed. There were no baseline differences across groups. The 30% responder rate primary analysis was not significant for nabiximols versus placebo (overall P = .59). A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall (P = .035), and specifically in the low-dose (P = .008) and medium-dose (P = .039) groups. In the low-dose group, results were similar for mean average pain (P = .006), mean worst pain (P = .011), and mean sleep disruption (P = .003). Other questionnaires showed no significant group differences. Adverse events were dose-related and only the high-dose group compared unfavorably with placebo. This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials. PERSPECTIVE: Nabiximols, a novel cannabinoid formulation, may be a useful add-on analgesic for patients with opioid-refractory cancer pain. A randomized, double-blind, placebo-controlled, graded-dose study demonstrated efficacy and safety at low and medium doses.

Methadone as an analgesic for patients with chronic pain in methadone maintenance treatment programs (MMTPs).

BACKGROUND: Limited case reports have suggested a role for methadone as an analgesic for chronic pain in patients maintained on methadone for treatment of opiate addiction. Patients with HIV are disproportionately represented in this population and often have severe, debilitating chronic pain syndromes of multiple etiologies, including cancer-related pain syndromes. OBJECTIVE: This study evaluated the safety and efficacy of initiating and maintaining additional methadone for chronic pain in HIV-positive patients with ongoing treatment for opiate addiction in methadone maintenance treatment programs (MMTPs). METHODS: We performed a retrospective chart review of 53 HIV/AIDS patients (36 male, 1 7 female; 24 with cancer) with diverse chronic pain syndromes who were followed in an HIV Pain Clinic and were currently enrolled in an MMTP. The outcome measure was pain, assessed using a numeric rating scale (0-10). Incidence of heroin use was also measured. RESULTS: The mean methadone dose initially prescribed for analgesia was approximately equal to 67 percent of the methadone dose used in the MMTP for addiction. Over the 12-month retrospective observation period, methadone was titrated to approximately 200 percent of the methadone maintenance dose. The mean pain score at initial visit to the Pain Clinic was 9.4 +/- 1.03. After methadone for analgesia has been administered for 1 month, the mean pain score decreased to 5.35 +/- 1.7 (p < 0.001), at 3 months, 4.8 +/- 1.3 (p < 0.001), at 6 months, 4.2 +/- 1.7 (p < 0.001), and at 12 months, 4.2 +/- 1.4 (p< 0.001). No serious adverse events or side effects were observed with methadone therapy for analgesia. CONCLUSION: HIV/AIDS patients with chronic pain enrolled in MMTPs achieved improved analgesia with no serious side effects when additional methadone was administered for pain relief. Further controlled studies are needed to confirm our findings and to establish the safety and efficacy of methadone therapy for chronic pain in this population.

Consensus guideline on parenteral methadone use in pain and palliative care.

Once used only as third-line therapy for chronic pain management, methadone is now being used as first- and second-line therapy in palliative care. The risks and stigma associated with methadone use are known, but difficulties with dosing methadone and lack of an established conversion protocol from other opiates have limited the access for patient populations who could potentially benefit from this medication. For palliative care patients, the benefits of methadone can far outweigh its risks. This article provides an overview and specific recommendations on the use of parenteral methadone in pain and palliative care, with a focus on the transition from hospital to home/hospice care. The goal of this consensus guideline is to assist clinicians who are providing chronic pain management in acute care hospital and nonhospital settings (i.e., hospice, long-term care facilities, and community) for patients with life-limiting illnesses, where the goals of care are focused on comfort (i.e., palliative care). The recommendations in this article intend to promote a standard of care involving the use of intravenous methadone with the aim of reaching a broader population of patients for whom this drug would provide important benefits.

Administration of morphine sulfate extended-release capsules via gastrostomy: dissolution study and case reports.

BACKGROUND: Patients with head and neck cancer undergoing radiation treatment develop painful mouth sores described as mucositis. There are grades I-IV of mucositis increasing in severity with grading. The aim of this study was to target patients who had painful mucositis at grade III-IV and treat their radiation-induced mucositis with gastrostomy administered morphine in an extended-release dosing form. OBJECTIVE: This study is important because many patients have breaks in radiation therapy secondary to severe painful mucositis and thus disrupt their potentially curative radiation treatment. DESIGN: The subjects were patients in a radiation clinic undergoing radiation for various head and neck cancers that had grade III-IV mucositis that was diagnosed by the clinician at the practice. The subjects were screened for mouth pain and sores when they came for radiation and they were then referred for study. The aim of the study was to measure the ability of the patient to administer the contents of the morphine extended-release capsules via gastrostomy tube was evaluated and the pain scores using a numerical rating scale (NRS). SETTING: The patients were seen in radiation oncology and screened for grade III or IV mucositis and then sent to the pain and palliative care clinic. MEASUREMENT: The measurements were to evaluate the feasibility of the patient's ability to administer the contents of the morphine extended-release capsule into the gastrostomy tube and to measure pain related to radiation-induced mucositis. The results were favorable in that the patients could self-administer the morphine using the described alternate route of administration and the pain scores reflected a trend toward pain relief by gastrostomy tube morphine delivery. However, a larger study sample will need to be investigated to determine efficacy in this type of delivery system for cancer pain relief in this population of patients undergoing radiation treatment for head and neck cancers.

A review of methylnaltrexone, a peripheral opioid receptor antagonist, and its role in opioid-induced constipation.

OBJECTIVES: Opioid medications are frequently used in pain and palliative care patients with malignancy to manage symptoms such as pain and dyspnea. However, opiates are associated with various side effects. Constipation is a particularly problematic and common side effect of opioid pharmacology. Opioid antagonists have been studied in the management of opioid-induced constipation. Methylnaltrexone (MNTX) is a peripheral opioid antagonist currently under clinical investigation. It offers the potential to reverse undesirable side effects without reversing analgesia. METHODS: This article attempts to review existing clinical data, focusing on antagonism of opioid-induced adverse effects on the gastrointestinal system. RESULTS: MNTX seems to be well tolerated with limited or transient side effects. MNTX has been shown to improve oral-cecal transit times in opioid treated patients, induce laxation in chronic opioid users, and neither reverses the analgesic effects of morphine nor cause withdrawal symptoms. SIGNIFICANCE OF RESULTS: Larger clinical trials of MNTX are still necessary to support its use as a standard for treatment of opioid-induced constipation.

Difficult pain syndromes: bone pain, visceral pain, and neuropathic pain.

Cancer pain is prevalent in approximately two thirds of all cancer patients and can undermine the quality of life in this patient population. Uncontrolled pain can cause physical as well as psychological distress in cancer patients. As the disease progresses in cancer, pain and suffering increase. Knowledge about pain management is paramount in the comprehensive treatment of cancer patients. Difficult cancer pain syndromes may arise from interruption of bone, viscera, and neural structures by malignant spread of the disease. Familiarity with opioids, adjuvants, and procedures that can abate pain in cancer patients is discussed in a practical manner for clinical application in this text.

The management of opioid-related sedation.

There are many side effects of opioids used for cancer and non-cancer pain, which can limit their use and vastly undermine the quality of life for patients. Sedation is a frequent and serious side effect of opioid analgesics, sometimes reported as fatigue or tiredness from patients. There are a number of specific therapies to control or manage these adverse effects, making it feasible to dose opioids to adequate analgesia with tolerable side effects. The balance between effect and side effects is the goal of chronic opioid pharmacotherapy. In particular, sedation commonly can be problematic in a patient who is taking opioids, to the extent that one may want to discontinue the medication and suffer with the pain rather than experience debilitating fatigue or sedation. When sedation clinically becomes excessive, measures should be taken to make it possible to continue treatment with analgesics with acceptable sedation management. There are many techniques to oppose sedation including simple antidotes, such as rest, exercise, and timing of opioid medications, and more complex solutions, such as opioid rotation and the use of psychostimulants or other classes of medications to counteract sedation. The treatment of opioid-induced sedation can be very effective and should be part of a skill set that the clinician can easily employ to enhance the quality of life of patients.

Measurement of QTc in patients receiving chronic methadone therapy.

Recent reports suggest that methadone may prolong the QTc interval and cause torsades de pointes. This study was conducted to evaluate the prevalence of QTc prolongation during oral methadone therapy and identify factors associated with prolongation. Patients receiving oral methadone as treatment for chronic pain or addiction were eligible for the study. One hundred four patients who were receiving > or = 20 mg methadone per day for > or = 2 weeks underwent electrocardiograms to measure QTc interval duration. Sixty-three (61%) patients were male and 63 (61%) were receiving methadone maintenance for opioid addiction. The mean (+/- SD) age was 45.3 +/- 9.4 years. The median (range) methadone dose was 110 mg/day (20-1200 mg/day); median (range) number of months on methadone was 12.5 months (1-444 months). The median (range) QTc interval was 428 msec (396-494 msec). Thirty-three percent had QTc prolongation (males 40%, females 20%; P=0.03). No patient had a QTc longer than 500 msec. Significant dose response was observed in males on methadone <12 months (rho=0.60, P=0.02). Our study suggests that methadone may prolong the QTc interval in specific subpopulations but poses little risk of serious prolongation.

The role of methadone in the treatment of moderate to severe cancer pain.

The World Health Organization recommends a step-by-step approach to the management of chronic cancer pain, called the analgesic ladder. Traditionally, morphine has been the prototypical opioid for chronic cancer pain because there is no ceiling effect or upper limit and it is a naturally occurring pure mu-opioid agonist. Occasionally, there are dose-limiting side effects and/or lack of efficacy. Opioid rotation is important because it improves analgesia and the side effect profile. Two principal reasons for failure of strong opioids are the presence of incident pain and/or neuropathic pain. Incident pain usually occurs in a patient with osseous metastases or another movement-related pain syndrome. Other reasons to rotate opioids are side effects such as intractable nausea and vomiting, sedation, dysphoria, delirium, and constipation, which are unresponsive to simple measures such as retitration, antiemetic agents, antipsychotic agents, psychostimulants, and laxatives. There are recent data that demonstrate that the accumulation of active metabolites in patients receiving common opioids such as morphine and hydromorphone are partly responsible for adverse effects. This premise has prompted clinicians and researchers to consider opioid rotation as a valid tool for cancer pain management to increase the probability of acceptable adverse effects with adequate analgesia. Methadone is an opioid agonist with a lack of known active metabolites, which are known to produce side effects with other opioids. Methadone has excellent bioavailability, making it a desirable analgesic agent for refractory types of cancer pain.

Outpatient management of sickle cell pain with chronic opioid pharmacotherapy.

We report our experience of providing chronic opioid pharmacotherapy on an outpatient basis to selected patients with frequent episodes of moderate-to-severe pain from sickle cell disease (SCD). Three cases illustrate our clinical experience in approximately 40 patients with sickle cell pain. Patients were seen at our sickle cell pain clinic at Beth Israel Hospital once each month for a three-hour visit. Visits included group music therapy and individual medical care, including comprehensive blood work and scheduling of medical tests when appropriate. Between visits, the pain and palliative care physicians followed patients on an as-needed basis. The SCD pain opioid pharmacotherapy protocol was modeled on a regimen used to treat malignant pain-typically a long-acting opioid in combination with a short-acting opioid, such as oral transmucosal fentanyl citrate (OTFC; Actiq) for breakthrough pain (BTP). Emergency department (ED) visits and hospital admissions were dramatically reduced in the three patients whose pain was managed by adapting the cancer pain model. During the year before their first visit to our pain clinic, the patients each had between six and 18 ED visits, which resulted in six- to 13 hospital admissions amounting to 32-182 inpatient days per patient. Each of the patients was prescribed a long-acting opioid (methadone, control-release oxycodone, or transdermal fentanyl) with a short-acting opioid for BTP from crises (oral transmucosal fentanyl citrate for two patients; short-acting oxycodone for one patient). Pain was well controlled. For each patient, hospital admissions were reduced to < or = 1 visit per year. These reduced levels of ED visits and hospital admissions have remained constant for more than three years.

Tolerability and effects of two formulations of oral transmucosal fentanyl citrate (OTFC; ACTIQ) in patients with radiation-induced oral mucositis.

BACKGROUND: Oral transmucosal fentanyl citrate (OTFC; ACTIQ) incorporates fentanyl into a lozenge allowing drug delivery through the oral mucosa resulting in rapid pain relief. OTFC is effective for breakthrough pain and could be particularly useful in patients with mucositis. METHODS: This randomized, double-blind, crossover study assessed two formulations of OTFC for tolerability in 14 patients with radiation-induced mucositis. On four separate days, patients with grade 3 or 4 mucositis received an OTFC unit 45 min before radiation treatment. Two units had a sweetened matrix formulation and two had a compressed powder formulation. One unit of each formulation contained 200 microg fentanyl and one was placebo. Tolerability, mucositis pain, and formulation preference were evaluated. Changes in oral mucosa were recorded. RESULTS: Both formulations of OTFC were well tolerated. There were no significant differences between formulations in tolerability, patient preference, or VAS pain scores. No changes in oral mucosa were noted. Common treatment-related adverse events included a burning sensation in the mouth, nausea, and vomiting. CONCLUSIONS: Both formulations of OTFC are well tolerated. The presence of fentanyl in either the sweetened matrix or the compressed powder did not alter tolerability or safety. The dose of fentanyl tested did not yield analgesia greater than placebo; future studies of OTFC efficacy in mucositis should evaluate higher doses than 200 microg.