Look before leaping: combined opioids may not be the rave

The use of combinations of potent opioids is a common clinical practice. The addition of one potent opioid to another has been recommended to reduce opioid side effects, improve pain control, and limit dose escalation of the first opioid. The advantages of using combined opioids have been reported to be relative to differences in receptor activation versus endocytosis (RAVE). However, the advantages and detriment to combining opioids are related to naturally occurring opioid receptor dimers. Dimers and oligomers result in a unique opioid pharmacodynamics which influence opioid binding, G protein interactions, desensitization, receptor trafficking, and endocytosis. The pharmacodynamics of dimers may lead to positive or negative cooperativity when two opioids are combined. The use of multiple opioids in practice can lead to increased risk for dosing errors, reduced patient compliance, increased drug interactions and cost. Opioid combinations should not be used until prospective randomized trials clarify the benefits and safety.A World Health Organization Demonstration Project     

Rotation to methadone after opioid dose escalation: How should individualization of dosing occur?

Methadone is a synthetic opioid agonist and N-methyl-D-aspartate (NMDA) receptor antagonist that is being increasingly used in pain management, particularly for pain that is resistant to conventional opioids. We describe two patients with neurotoxic side effects on escalating doses of parenteral hydromorphone with uncontrolled cancer pain who were successfully converted to oral methadone at a dose much smaller than predicted. The phenomenon of increasing pain despite opioid dose escalation is discussed and the rationale for the use of methadone in this situation is described. While methadone is useful for patients with unremitting pain on another opioid, existing conversion regimens do not specifically take into account the setting of dose escalation. Clinical guidelines for rotation to methadone after dose escalation of the previous opioid are needed to avoid toxicity including respiratory depression. A possible conversion method for rotation to methadone for patients with escalating pain and opioid use is suggested.     

Critical issues on opioids in chronic non-cancer pain: an epidemiological study

The aim of the study was epidemiologically to evaluate the long-term effects of opioids on pain relief, quality of life and functional capacity in long-term/chronic non-cancer pain. The study was based on data from the 2000 Danish Health and Morbidity Survey. As part of a representative National random sample of 16,684 individuals (>16 years of age), 10,066 took part in an interview and completed a self-administered questionnaire. Cancer patients were excluded. The interview and the self-administered questionnaire included questions on chronic/long-lasting pain (>6 months), health-related quality of life (SF-36), use of the health care system, functional capabilities, satisfaction with medical pain treatment and regular or continuous use of medications. Participants reporting pain were divided into opioid and non-opioid users. The analyses were adjusted for age, gender, concomitant use of anxiolytics and antidepressants and pain intensity. Pain relief, quality of life and functional capacity among opioid users were compared with non-opioid users. Opioid usage was significantly associated with reporting of moderate/severe or very severe pain, poor self-rated health, not being engaged in employment, higher use of the health care system, and a negative influence on quality of life as registered in all items in SF-36. Because of the cross-sectional nature causative relationships cannot be ascertained. However, it is remarkable that opioid treatment of long-term/chronic non-cancer pain does not seem to fulfil any of the key outcome opioid treatment goals: pain relief, improved quality of life and improved functional capacity.     

Efficacy of opioids for chronic pain: a review of the evidence

Opioid therapy for chronic pain has been popularized over the past few decades, and a concern has arisen that the analgesic efficacy of opioids is not always maintained over prolonged courses of treatment despite dose escalation and stable pain. Considering the potentially serious adverse effects of opioids, the idea that pain relief could diminish over time may have a significant impact on the decision to embark on this therapy, especially in vulnerable individuals. Possible loss of analgesic efficacy is especially concerning, considering that dependence may make it hard to withdraw opioid therapy even in the face of poor analgesia. This article first reviews the evidence on opioid efficacy when used for the treatment of chronic pain, and concludes that existing evidence suggests that analgesic efficacy, although initially good, is not always sustained during continuous and long-term opioid therapy (months to years). The theoretical basis for loss of analgesic efficacy over time is then examined. Mechanisms for loss of analgesic efficacy proposed are pharmacologic tolerance, opioid-induced hyperalgesia, subtle and intermittent withdrawal, and a number of psychologic factors including loss of the placebo component.     

The Addition of Tramadol as a Second Opioid May Improve Pain Relief in Severe Osteoarthritis: A Prospective Study

Background: Opioid combination has been shown to reduce the need for escalating doses for the treatment of cancer pain. A prospective study was planned to evaluate the addition of tramadol to a stronger opioid for the treatment of severe pain as a result of osteoarthritis, previously uncontrolled by non‐opioid analgesics or weak opioids. Methods: All subjects received tramadol 200 mg and tizanidine 2 mg. At 2 weeks, tramadol was discontinued for patients still reporting poor pain relief (effectiveness ≤50%), and a stronger opioid was titrated to a morphine equivalent amount (MEA) of 40–60 mg orally. After two additional weeks, patients were then divided into two groups: the Strong Opioid Group (SO) and the Tramadol plus the Strong Opioid Group (TSO). The SO group was allowed to escalate opioid dose for lack of effectiveness; the TSO group received tramadol 150 mg daily, thereafter additional strong opioid titration was allowed. Results: A total of 74 patients were studied: SO (n = 40) and TSOG (n = 34). All patients eventually achieved pain relief quality, with both groups reporting similar Karnofsky Performance Scale effectiveness. The SO group achieved satisfactory pain relief (>50%) at an average daily oral MEA of 120 mg. TSO subjects achieved satisfactory pain relief (>50%) at an average daily oral MEA of 95 mg. Discussion: The addition of tramadol provided a synergistic effect resulting in a 30‐mg decrease in necessary morphine equivalents with fewer opioid‐related adverse effects.     

Opioid escalation in patients with cancer pain: the effect of age

Elderly people are commonly considered more susceptible to opioid effects. However, no data regarding the need for opioid escalation in patients already receiving opioids for the management of chronic pain are available. The purpose of this study was to evaluate the differences between younger and older patients during the crucial phase of opioid titration. One hundred consecutive patients with cancer pain requiring further opioid dose refinement were recruited for this cohort study. Pain intensity, dose of opioids, number of opioids used (need to switch), routes of administration used, and opioid-related symptoms were measured from admission until dose stabilization. Opioid escalation indexes (OEIs) were calculated. For the purpose of analysis, patients were divided into three age groups (<65, 65-74, 75 or over). Despite differences in opioid doses at admission (lower in older patients), no differences were found in routes, need to switch, OEI, or other parameters between younger and older patients. Similarly, adverse effects did not significantly differ between the three groups, although an overall distress score worsened in older patients during acute titration and then improved at stabilization time. These data contradict the assumption that older patients who already receive opioids are more susceptible than younger adults to opioid effects during opioid titration. Although the elderly require lower doses, opioid effects do not appear to vary with age in this population. However, the group of patients over 75 was relatively small and data should be interpreted with caution. Careful titration based on the individual response seems appropriate irrespective of age.     

Opioid-induced or pain relief-reduced symptoms in advanced cancer patients?

BACKGROUND: While opioids in increasing doses may produce adverse effects, the same adverse effects may be associated with poor pain control. Moreover, in the clinical setting symptomatic treatment and illness may balance the outcome of opioid titration. Some adverse effects may tend to disappear continuing the treatment in a long-term period. AIMS: The aim of this study was to monitor the effects of a rapid opioid titration combined with symptomatic treatment in patients with poor relief and to monitor these changes in the following period of 20 days. METHODS: A consecutive sample of 35 patients admitted to an acute Pain Relief and Palliative Care Unit were titrated with opioids, according to a department policy, allowing administration of parenteral opioids to assist opioid titration with oral or transdermal opioids. RESULTS: Thirty-three patients were followed up for the period of the study. Pain was adequately controlled and doses were opioid doses were stable after a mean of 40 h. Opioid escalation index (OEI) was extremely high initially, and then progressively declined at the following study intervals. Weakness and nausea and vomiting did not change, as well as confusion and appetite. Drowsiness, constipation and dry mouth significantly increased and then did not change, although a significant decrease in drowsiness was subsequently observed. Well-being improved some weeks after opioid stabilization. In multivariate analysis, drowsiness and dry mouth were correlated to opioid doses. CONCLUSION: The effects reported were often due to multiple causes. A rapid decrease in pain intensity induced by rapid opioid titration does not produce changes in weakness, nausea and vomiting, appetite. While constipation appears the most relevant problem, resistant to common symptomatic treatment, drowsiness initially produced by acute opioid dose increase and the achievement of pain relief, tends to spontaneously decrease, probably as the result of late tolerance. Improved well-being may be the late positive effect of pain relief, also influenced by the setting of home care.     

Assessment of pain control in cancer patients during the last week of life: comparison of health centre wards and a hospice

The aim of this prospective study was to assess the quality of cancer pain control during the last week of life in two different types of units for terminal cancer patients in Finland: on health centre wards (N=20) and in a hospice (N=30). Pain scores (VAS), defined daily doses (DDD), routes of administration and costs of pain medication were analysed for each patient. On the 7th-last day before death and during the very last day of life (24 h), respectively, the following results were seen: proportions of patients using strong opioids 64% and 84%, mean equivalent parenteral morphine doses of strong opioids 42 mg and 57 mg, mean pain scores (VAS 0-10) 3.11 and 3.05, mean daily cost of pain medication 2.22 and 2.90 euros. Pain control was thus found to be good with low costs. On the 7th day before death strong opioids were used for a greater proportion of patients on the health centre wards. Differences were also seen in the routes of administration used for strong opioids. Weak opioids were used more in the hospice and NSAIDs, more on the health centre wards. However, no differences were found either in the mean doses of strong opioids or in the quality or the costs of pain control between the health centre wards and the hospice.     

Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia

Effective management of chronic pain has become an increasingly critical issue in health care. Opioid agonists are among the most effective analgesics available for reducing pain perception; however, their chronic use is controversial. This is primarily due to regulatory barriers, misunderstandings about pain management among primary caregivers, fear of adverse side effects, and misconceptions about the potential risks of addiction. Short-acting opioids provide effective analgesia for acute pain but should be avoided as primary analgesics for chronic pain management. Long-acting opioids have greater utility than short-acting opioids in treating chronic pain in patients with consistent pain levels. Results of studies show that improved quality of life is directly related to the use of long-acting opioids in patients with chronic pain of both cancer and noncancer etiology. Short-acting opioids may be used during the initial dose titration period of long-acting formulations and as rescue medication for episodes of breakthrough pain. Clinical experience reveals that selection of an effective pain regimen for the patient with chronic pain, combined with aggressive management of side effects, leads to improved overall functioning and quality of life.     

Management of common opioid-induced adverse effects

Opioid analgesics are useful agents for treating pain of various etiologies; however, adverse effects are potential limitations to their use. Strategies to minimize adverse effects of opioids include dose reduction, symptomatic management, opioid rotation, and changing the route of administration. Nausea occurs in approximately 25 percent of patients; prophylactic measures may not be required. Patients who do develop nausea will require antiemetic treatment with an antipsychotic, prokinetic agent, or serotonin antagonist. Understanding the mechanism for opioid-induced nausea will aid in the selection of appropriate agents. Constipation is considered an expected side effect with chronic opioid use. Physicians should minimize the development of constipation using prophylactic measures. Monotherapy with stool softeners often is not effective; a stool softener combined with a stimulant laxative is preferred. Sedation and cognitive changes occur with initiation of therapy or dose escalation. Underlying disease states or other centrally acting medications often will compound the opioid's adverse effects. Minimizing unnecessary medications and judicious use of stimulants and antipsychotics are used to manage the central nervous system side effects. Pruritus may develop, but it is generally not considered an allergic reaction. Antihistamines are the preferred management option should pharmacotherapy treatment be required.     

Opioid consumption in a tertiary hospital setting over an 8-year timeframe--a potential resource for tracking trends in pain management

Opioid consumption by countries and health care organizations can be regarded as a marker of the quality of pain management. However, there are only limited data on opioid consumption in hospital settings. Objective and reliable data can be obtained by monitoring direct opioid consumption within a hospital, and then that data can be analyzed for identifying trends and directions to assist in guiding improved pain treatment within the hospital. This article tracks opioid consumption in a tertiary hospital over an 8-year period and by comparing the data to the consumption during the previous decade, it highlights trends and tendencies in the use of opioids as a potential indicator of pain management within this facility.     

Eingeschränkte Wirksamkeit von Opioiden bei chronischen muskuloskelettalen Schmerzen

After excluding malignant disease in 21 patients with unremitting strong pain of the musculoskeletal system despite long-term opioid medication, the opioids were withdrawn to search for reasons of the limited effectiveness of the opioids.The opioid withdrawal was integrated in multimodal pain coping therapy. Besides the somatic diagnoses, pain-relevant psychosomatic diagnoses were evaluated with the structured clinical interview for DSM-IV (SCID). At the time of admission and discharge pain medication, physical functions, mood, and pain intensity were recorded.In the SCID interview, all patients were diagnosed with a relevant comorbid psychiatric condition (pain disorder, anxiety, depression). Despite reduction of the opioid medication, there was no increase of pain, but an improvement of the physical functions.In patients with chronic pain of the musculoskeletal system and limited effectiveness of opioid medication, psychosomatic comorbidities should be evaluated. Instead of continued and increased opioid medication, pain coping strategies and opioid withdrawal should be tested.     

Assessment of physiatrists' knowledge and perspectives on the use of opioids: review of basic concepts for managing chronic pain.

Previous studies of physicians have elucidated knowledge gaps and misconceptions about the use of opioids for the treatment of chronic pain. The recent approval of a pain management subspecialty certification for physiatrists will create higher expectations of the field regarding the treatment of chronic pain. Five hundred randomly chosen physiatrists were surveyed with a 50.6% response rate. Ninety-eight percent of respondents treat patients with chronic noncancer pain diagnoses, and 37% occasionally treat patients with cancer-related pain. Seventy percent of respondents underestimated the percentage of patients with cancer-related pain that could experience relief with oral analgesics. Only 17% underestimated the percentage of advanced cancer patients that experience significant pain. Eight percent of respondents incorrectly answered that a patient, regardless of diagnosis, would become addicted to opioids by taking an opioid daily. Only 25% identified the correct definition of addiction. Questions regarding side effects revealed that 10% of respondents incorrectly believed that opioid-induced respiratory depression is common in patients whose oral morphine dose exceeds 100 mg per day. Eighty percent of respondents preferred long-acting preparations, and 92% preferred set dosing schedules for the treatment of chronic pain. Rapidly evolving concepts regarding the implementation of pharmacologic regimens for chronic pain diagnoses require health care professionals who are trained to administer these treatments. Overall, the survey results are encouraging regarding physiatrists' knowledge about the use of opioids to treat patients with chronic pain.