Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid. A retrospective analysis of 273 patients observed at a single center

 The charts of 273 cancer patients were retrospectively analyzed in order (1) to evaluate the frequency of opioid change (OCH) when adjuvants (antiemetics/laxatives) were administered on a regular basis and co-analgesic medication as indicated by the specific type of pain, (2) to define risk factors for the request of OCH, and (3) to reveal settings in which OCH may not be recommended as a first-line therapeutic intervention. Opioids used included morphine, fentanyl, l-methadone, and buprenorphine. Out of 273 patients, 103 changed opioids at least once, with a success rate of 65%. The indications for the OCH were insufficient analgesia in 43%, intolerable side effects in 20%, both in 15%, and other reasons in 22% of patients. The frequency of OCH was not influenced by the routine use of adjuvants or co-analgesics except corticosteroids, which raises queries about the concept of an opioid-sparing effect of co-analgesics. The occurrence of intolerable side effects is thought not to be dose dependent so much as to reflect differences in the individual tolerability of a distinct opioid for whatever reason (genetically fixed or individually acquired pharmacodynamic or kinetic properties). Moreover, there was strong evidence for the existence of an unpredictable and incomplete cross-tolerance between opioids, which meant careful titration of the new opioid was required after OCH. The overall frequency of OCH was similar to that observed in previous studies in spite of the documented addition of adjuvants and co-analgesics. This retrospective study supports the notion that opioid rotation must be retained as an essential therapeutic option even with optimized adjuvant and co-analgesic regimens. Published online: 7 June 2000     

The effects of immediate-release morphine on cognitive functioning in patients receiving chronic opioid therapy in palliative care

Morphine and other potent opioids are frequently used in palliative care and pain management. When sustained-release (SR) opioids do not provide adequate background analgesia, additional immediate-release (IR) opioid (e.g. short-acting morphine) may be required to alleviate breakthrough or episodic pain. Despite the frequent use of IR morphine on top of SR opioids, little is known about the effects of such treatment on patients' everyday cognitive functioning. This study therefore used a double-blind, placebo-controlled, cross-over design to assess cognitive functioning in 14 patients receiving palliative care. All patients were taking SR opioid preparations and required 相似文献   

A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997-2002

This study updates a previous analysis of trends in medical use and abuse of opioid analgesics, and provides data from 1997 through 2002. Two research questions were evaluated: 1) What are the trends in the medical use and abuse of frequently prescribed opioid analgesics used to treat severe pain, including fentanyl, hydromorphone, meperidine, morphine, and oxycodone? 2) What is the abuse trend for opioid analgesics as a class compared to trends in the abuse of other drug classes? Results demonstrated marked increases in medical use and abuse of four of the five studied opioid analgesics. In 2002, opioid analgesics accounted for 9.85% of all drug abuse, up from 5.75% in 1997. Increase in medical use of opioids is a general indicator of progress in providing pain relief. Increases in abuse of opioids is a growing public health problem and should be addressed by identifying the causes and sources of diversion, without interfering with legitimate medical practice and patient care.     

An Italian survey on the attitudes in treating breakthrough cancer pain in hospice

As recognition and treatment of breakthrough cancer pain (BcP) depend on the education and knowledge of palliative care physicians, it is important to systematically explore the attitudes of palliative care physicians in hospices or palliative care units. The aim of this study was to assess the knowledge and attitudes of hospice physicians in Italy regarding BcP and its treatment. All hospices existing in Italy were interviewed to gather information about provision of BP medication, drugs of choice, preferred route of administration, methods to choose the dose, and choice of BcP medication based on opioid administered for background analgesia. Of 158 hospices registered, 122 centers agreed with the interview (77.2%). Morphine was more frequently used, either orally or parenterally. In some hospices, oral transmucosal fentanyl (OTFC) was unavailable. Most physicians provided doses of opioids proportional to the opioid basal regimen, independently of the preferred opioid or the route of administration. The choice of dose titration was equally used in patients who were prescribed OTFC or parenteral morphine. The choice of breakthrough medication on the basis of opioid basal regimen was equally distributed. These findings suggest the need for improved education on behalf of physicians on the assessment and treatment of BcP, particularly in a potentially specialized setting, such as palliative care units. The choice of BcP medications should be based on the best cost-efficacy ratio rather than solely on economical considerations.     

Mitigating opioid errors in inpatient palliative care: A qualitative study

BackgroundOpioids are a high-risk medicine used in high doses and volumes in specialist palliative care inpatient services to manage palliative patients’ pain and other symptoms. Despite the high volume of opioid use in this care setting, serious errors with opioids are exceedingly rare. However, little is known about the factors that mitigate opioid errors in specialist palliative care inpatient services.AimTo explore palliative care clinicians’ perceptions of factors that mitigate opioid errors in specialist palliative care inpatient services.Methods and designA qualitative study using focus groups and semi-structured interviews.Participants and settingRegistered nurses, doctors, and/or pharmacists (‘clinicians’) who were involved with and/or had oversight of the services’ opioid delivery and/or opioid quality and safety processes, employed by one of three specialist palliative care inpatient services in metropolitan NSW.FindingsFifty-eight participants took part in this study, three-quarters (76%) of which were palliative care nurses. A positive opioid safety culture was central to mitigating opioid errors in specialist palliative care inpatient services. This culture of opioid safety was founded on clear and consistent safety messages from leadership, clinicians empowered to work together and practise safely, and a non-punitive approach to errors when they occurred. The clinical nurse educator was seen as pivotal to shaping, driving and reinforcing safe opioid delivery practices across the palliative care service.ConclusionCreating and sustaining a positive opioid safety culture, and promoting a non-punitive approach to opioid error and reporting, is essential to mitigating opioid errors in the specialist palliative care inpatient setting.     

A review of oral transmucosal fentanyl citrate: potent, rapid and noninvasive opioid analgesia

The physiochemical characteristics of the potent synthetic opioid agonist fentanyl make it ideal for noninvasive transmucosal delivery. Studies of oral transmucosal fentanyl citrate (OTFC), a candied matrix formulation administered orally as a palatable lozenge on a stick, have investigated and determined this analgesic's pharmacokinetics and pharmacodynamics in a number of clinical settings, including premedication before surgery, acute analgesia for painful medical procedures, and, most recently, for the control of breakthrough cancer pain. The onset to meaningful pain relief in patients with acute pain from surgery or breakthrough pain from cancer is between 5 and 10 minutes after initiating OTFC use, equivalent to intravenous morphine. Analgesic dose equivalency studies suggest that OTFC is, on average, about 10 times more potent than morphine, although, in randomized, controlled, and blinded studies, many patients who were using relatively high doses of opioid anlagesics on an around the- clock schedule for control of cancer pain reported that even a low dose of OTFC (i.e., 200 microg) provided adequate relief from breakthrough pain. Side effects from OTFC are similar in character and frequency to other opioids, including sedation, nausea, and pruritus. These effects appear to wane rapidly with repeated use of this medication. To date there have been no reported serious adverse events in any of the population groups studied or treated with OTFC.     

Comparison between intravenous morphine versus fentanyl in acute pain relief in drug abusers with acute limb traumatic injury

BACKGROUND: Rapid and effective pain relief in acute traumatic limb injuries (ATLI) is one of the most important roles of emergency physicians. In these situations, opioid addiction is an important concern because of the dependency on opioids. The study aims to compare the effectiveness of intravenous (IV) fentanyl versus morphine in reducing pain in patients with opioid addiction who suffered from ATLI. METHODS: In this double-blind randomized clinical trial, 307 patients with ATLI, who presented to the emergency department (ED) from February 2016 to April 2016, were randomly divided into two groups. One group (152 patients) received 0.1 mg/kg IV morphine. The other group (155 patients) received 1 mcg/kg IV fentanyl. Patients’ demographic data, pain score at specific intervals, vital signs, side effects, satisfaction and the need for rescue analgesia were recorded. RESULTS: Eight patients in the morphine group and five patients in the fentanyl group were excluded. Pain score in the fentanyl group had a significant decrease at 5-minute follow-up (P value=0.00). However, at 10, 30, and 60-minute follow-ups no significant differences were observed between the two groups in terms of pain score reduction. The rescue analgesia was required in 12 (7.7%) patients in the fentanyl group and in 48 (31.6%) patients in the morphine group (P value=0.00). No significant difference was observed regarding side effects, vital signs and patients’ satisfaction between the two groups. CONCLUSION: Fentanyl might be an effective and safe drug in opioid addicts suffering from ATLI.     

Use of the mixed agonist–antagonist nalbuphine in opioid based analgesia

Opiate analgesics provide effective pain relief and are widely used for control of mild to severe pain. The well-known side effects of the mu-agonist opioids, including pruritis, nausea/emesis, constipation, urinary retention, respiratory depression, excessive sedation, and the development of tolerance and dependence, are occasionally problematic. Here we review use of the mixed opioid agonist–antagonist nalbuphine in opioid analgesia with a view to its potential advantages. Used as the sole opioid analgesic, it can satisfactorily cover mild to moderate pain with a low incidence of the common opioid side effects. With care, it can be used concurrently with the more commonly employed mu-opioid agonists (e.g. morphine, hydromorphone, fentanyl), yielding good analgesia while simultaneously decreasing the incidence and severity of mu-agonist side effects. This paper provides information sufficient to enable the practitioner to determine whether nalbuphine might be a useful addition to his/her pharmacopoeia.     

Incidence of constipation associated with long-acting opioid therapy: a comparative study

BACKGROUND: Opioid therapy plays a key role in the management of chronic pain. Constipation is one of the more frequently occurring adverse effects associated with opioid therapy. METHODS: A retrospective cohort design study was conducted to determine the incidence of constipation in chronic pain patients who received three different long-acting opioids (transdermal fentanyl, oxycodone HCl controlled-release [CR], or morphine CR) for malignant or nonmalignant chronic pain. The data source was claims data (January 1996 through March 2001) from a 20% random sample of the California Medicaid (Medi-Cal) database. Claims data were from adult patients with chronic pain (malignant or nonmalignant) who had no prior diagnosis of constipation and no prior usage of long-acting opioids for at least 3 months before the observation period. Patients were followed for at least 3 months after the initiation of opioid therapy. ICD-9 code for diagnosis of constipation was the main outcome variable. Crude rates of constipation, annual incidence density, relative risk, and adjusted odds ratios were compared. RESULTS: A total of 1,836 patients (601 receiving transdermal fentanyl, 721 receiving oxycodone CR, and 514 receiving morphine CR) were included in the analysis. Crude (unadjusted) rates of constipation were 3.7% for transdermal fentanyl, 6.1% for oxycodone CR, and 5.1% for morphine CR (P > 0.05). Transdermal fentanyl had a lower annual incidence density and risk of constipation than oxycodone CR and morphine CR (P > 0.05). After adjusting for confounding variables, including race and supplemental opioid use, the adjusted risk of constipation was 78% greater in the oxycodone CR group (P = 0.0337) and 44% greater in the morphine CR group (P = 0.2242) than in the transdermal fentanyl group. CONCLUSION: In this population, patients receiving transdermal fentanyl had a lower risk of developing constipation compared with those receiving oxycodone CR or morphine CR.     

Pain and pain treatments in European palliative care units. A cross sectional survey from the European Association for Palliative Care Research Network

The Research Network of the European Association for Palliative Care (EAPC) performed a survey of 3030 cancer patients from 143 palliative care centres in 21 European countries. The survey addressed pain intensity and the use of non-opioid analgesics, adjuvant analgesics and opioids. Patients were treated with analgesics corresponding to the WHO pain ladder step I (n = 855), step II (n = 509) and step III (n = 1589). The investigators assessed 32% of the patients as having moderate or severe pain. In general there were small differences between pain intensities across different countries. Cancer primary sites and the presence of metastasis had only minor influences on pain intensity. The most frequently used non-opioid analgesics were NSAIDs (26%) and paracetamol (23%). Adjuvant analgesics or co-analgesics used by >1% of the patients were corticosteroids (39%), tricylic antidepressants (11%), gabapentin (5%), bisphosphonates (4%), clonazepam (2%), carbamazepine (4%) and phenytoin (2%). The use of non-opioid analgesics and co-analgesics varied widely between countries. Opioids administered for mild to moderate pain were codeine (8%), tramadol (8%), dextropropoxyphene (5%) and dihydrocodeine (2%). Morphine was the most frequently used opioid for moderate to severe pain (oral normal release morphine: 21%; oral sustained-release morphine: 19%; i.v. or s.c. morphine: 10%). Other opioids for moderate to severe pain were transdermal fentanyl (14%), oxycodone (4%), methadone (2%), diamorphine (2%) and hydromorphone (1%). We observed large variations in the use of opioids across countries. Finally, we observed that only a minority of the patients who used morphine needed very high doses.     

The use of fentanyl buccal tablets for breakthrough pain by using doses proportional to opioid basal regimen in a home care setting

The dose of rapid onset opioids to be given for breakthrough cancer pain (BTcP) is controversial. Dose proportional to the basal opioid regimen seem to be safe and effective in hospital units. However, data in other less protected settings, like home care, are lacking. The aim of this open-label study was to assess the efficacy and safety in a group of patients with BTcP followed at home, after giving a dose of fentanyl buccal tablets (FBT) proportional to the opioid basal regimen, skipping the steps for dose titration. Consecutive patients admitted to a home care program presenting BTcP episodes and receiving stable doses of opioids for background pain were selected. Data from four consecutive episodes of BTcP were collected. For each episode, patients were instructed to routinely collect changes in pain intensity and severe adverse effects when pain got severe (T0) and to reassess the same items 15 min after FBT, given as a rescue medication in doses proportional to the daily opioid doses used for background pain (T15). One hundred twenty episodes of BTcP were recorded in 30 patients. One hundred eight episodes were defined as successfully treated, while 12 episodes required a further administration of opioids. Pain intensity significantly decreased at T15 (p?<?0.001). In 95.5 and 90.8 % of episodes treated, there was a reduction in pain intensity of more than 33 and 50 %, respectively. No relevant adverse effects were recorded, even in older patients. This study suggests that FBT given in doses proportional to the basal opioid regimen for the management of BTcP is very effective and safe in clinical practice in the home care setting.     

Sustained‐release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management

Purpose: The aim of this study was to compare the analgesic and adverse effects, doses, as well as cost of opioid drugs, supportive drug therapy and other analgesic drugs in patients treated with oral sustained‐release morphine, transdermal fentanyl, and oral methadone. Patients and methods: One hundred and eight cancer patients, no longer responsive to opioids for moderate pain, were selected to randomly receive initial daily doses of 60mg of oral sustained‐release morphine, 15mg of oral methadone, or 0.6mg (25μg/h) of transdermal fentanyl. Oral morphine was used as breakthrough pain medication during opioid titration. Opioid doses, pain intensity, adverse effects, symptomatic drugs, were recorded at week intervals for 4weeks. Costs of opioid therapy, supportive drugs, and other analgesic drugs were also evaluated. Results: Seventy patients completed the 4weeks period of study. Five, five, and four patients, treated with oral morphine, transdermal fentanyl, and oral methadone, respectively, required opioid switching. No differences in pain and symptom intensity were observed. Opioid escalation index was significantly lower in patients receiving methadone (p<0.0001), although requiring up and down changes in doses. At the doses used, methadone was significantly less expensive (p<0.0001), while the use and costs of supportive drugs and other analgesics were similar in the three groups. No relevant differences in adverse effects were observed among the groups during either the titration phase and chronic treatment. Conclusion: All the three opioids used as first‐line therapy were effective, well tolerated, and required similar amounts of symptomatic drugs or co‐analgesics. Methadone was significantly less expensive, but required more changes, up and down, of the doses, suggesting that dose titration of this drug requires major clinical expertise.     

Opioids for the management of breakthrough cancer pain in adults: a systematic review undertaken as part of an EPCRC opioid guidelines project

The usual management of cancer related breakthrough pain is with supplemental doses of analgesics (commonly opioids) at a dose proportional to the total around-the-clock opioid dose. The aim of this review, undertaken as part of a European Palliative Care Research Collaborative (EPCRC) project, to update the EAPC guidelines on opioid analgesics in cancer pain was to determine the evidence for the utility of opioids in the management of breakthrough pain in patients with cancer. Randomized controlled trials of opioids used as rescue medication were identified using electronic search strategies. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, and patient satisfaction. The date of the final search was 31 July 2009. Eight studies (790 patients) met the inclusion criteria. Most studies investigated rescue medication delivery via the buccal or nasal transmucosal routes. Intravenous morphine has been compared with the transmucosal route and the two found to be effective. The oral route has not been formally tested although found to be an inferior comparator in one study. Most studies showed no meaningful relationship between the effective dose of transmucosal opioid and the around-the-clock scheduled medication or the previous rescue medication, although one study found a fixed proportion of either intravenous morphine or transmucosal fentanyl to be efficacious.     

Switching opioids to transdermal fentanyl in a clinical setting

INTRODUCTION: The use of transdermal fentanyl is gaining in importance in the management of cancer pain. We describe the reasons for switching opioid medication to transdermal fentanyl in a pain management unit. METHODS: Case records of patients treated with transdermal fentanyl in our pain clinic were evaluated retrospectively. Conversion ratios were calculated from the opioid dosage before and after conversion. Pain intensities were assessed on a numeric rating scale (NRS 0: no pain, 10: worst pain imaginable). RESULTS: From October 1995 to December 1997 101 patients received transdermal fentanyl. Thirty-six patients had been treated with transdermal fentanyl before admission to our pain clinic, and relevant information was missing for one patient, so 64 patients were evaluated. Opioid therapy was switched to transdermal fentanyl during in-patient treatment for 53 patients and during out-patient treatment for 11 patients. Before conversion patients were treated with slow-release morphine (48%), immediate-release morphine (17%), buprenorphine (11%), tramadol (11%), levomethadone (5%), tilidine/naloxone (5%) and piritramid (3%). Reasons for opioid rotation were inadequate pain relief ( 33%), the patients' wish to reduce oral medication (20%), gastrointestinal side effects such as nausea (31%), vomiting (13%) and constipation (19%), dysphagia (27%) or others. Reduction of side effects was reported by 10 of 19 patients. In 12 of 21 patients, in whom the medication was switched because of inadequate pain relief, a reduction in pain intensity was reported. DISCUSSION: Conversion to transdermal therapy may readjust the balance between opioid analgesia and side effects. The opioid switch resulted in more pain relief or fewer side effects in half of the patients. A proposed equianalgesic conversion ratio between 70:1 and 100:1 from oral slow-release morphine to transdermal fentanyl can be confirmed by our data. Conversion rates from other opioids to transdermal fentanyl are suggested.     

Risks for possible and probable opioid misuse among recipients of chronic opioid therapy in commercial and medicaid insurance plans: The TROUP Study

The use of chronic opioid therapy (COT) for chronic non-cancer pain (CNCP) has increased dramatically in the past two decades. There has also been a marked increase in the abuse of prescribed opioids and in accidental opioid overdose. Misuse of prescribed opioids may link these trends, but has thus far only been studied in small clinical samples. We therefore sought to validate an administrative indicator of opioid misuse among large samples of recipients of COT and determine the demographic, clinical, and pharmacological risks associated with possible and probable opioid misuse. A total of 21,685 enrollees in commercial insurance plans and 10,159 in Arkansas Medicaid who had at least 90 days of continuous opioid use 2000–2005 were studied for one year. Criteria were developed for possible and probable opioid misuse using administrative claims data concerning excess days supplied of short-acting and long-acting opioids, opioid prescribers and opioid pharmacies. We estimated possible misuse at 24% of COT recipients in the commercially insured sample and 20% in the Medicaid sample and probable misuse at 6% in commercially insured and at 3% in Medicaid. Among non-modifiable factors, younger age, back pain, multiple pain complaints and substance abuse disorders identify patients at high risk for misuse. Among modifiable factors, treatment with high daily dose opioids (especially >120 mg MED per day) and short-acting Schedule II opioids appears to increase the risk of misuse. The consistency of the findings across diverse patient populations and the varying levels of misuse suggest that these results will generalize broadly, but await confirmation in other studies.     

Exploring beliefs and practice of opioid prescribing for persistent non-cancer pain by general practitioners.

Persistent non-cancer pain is a common reason for consultation in primary care but treatment options, including non-opioid analgesics, are limited, and neither strong evidence nor established guidelines address when and how primary care doctors should prescribe opioid analgesics for persistent non-cancer pain. The aim of this study was to investigate associations between doctors' prescribing patterns for persistent non-cancer pain in primary care and their personal and practice characteristics and beliefs about appropriateness and risks of opioids. A pilot survey sampled beliefs concerning the need for and risks of opioid prescribing for persistent non-cancer pain among volunteers from primary care practices and postgraduate educational events, using a self-report questionnaire, and related these beliefs to their reported opioid prescribing. One quarter of the sample prescribed no opioids for persistent non-cancer pain. Prescribing opioids was predicted by moderate belief in the appropriateness of opioids within certain constraints, and to a lesser extent by younger age. While some beliefs distinguished prescribers from non-prescribers, predicting non-prescribing was poor. Both prescribers and non-prescribers expressed concern about the risks of opioids. In addition, most primary care doctors were dissatisfied with their training on pain; few had prescribing guidelines; and neither training nor guidelines influenced prescribing. In conclusion, whether or not GPs prescribe opioids for persistent non-cancer pain is mainly determined by their personal beliefs about appropriateness of opioids for this problem.     

The effectiveness of transdermal fentanyl in palliative care

Current literature suggests that transdermal fentanyl is efficacious in relieving cancer-related pain with less opioid-related constipation than morphine for patients in the palliative care setting. However, randomised controlled trials are needed to study the drug's efficacy compared with other level-three opioids that are used to manage cancer-related pain in palliative care.