Short- or long-acting opioids in chronic non-malignant pain: Which are better?”
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Background Chronic pain affects 15-30 % of the western population. Chronic pain is associated with a reduced quality of life for the individual, an increased consumption of healthcare resources and a loss of productivity and is hence a condition that incurs high costs for both the individual and society. Chronic pain patients comprise a very diverse group and their need for treatment is accordingly diverse. Those most severely affected require a multidisciplinary approach that may include pharmacotherapy. Numerous types of analgesics are available. Some patients require strong analgesics and the opioids have been reported to provide about 30 % relief in chronic pain both from neuropathic and nociceptive origins in selected patient populations. Opioids exert many side effects, with nausea, constipation and sedation being the most common. Additional, more serious side effects include respiratory depression, problematic opioid use, tolerance and addiction. Prescribing opioids for chronic nonmalignant pain is a difficult task, and many guidelines have been published to help practitioners achieve a safe and effective prescription practice. Many of the guidelines recommend the use of long-acting opioids for the treatment of chronic non-malignant pain because long-acting formulations are believed to pose less of a risk of causing addiction and problematic opioid use. They are also hypothesized to provide improved and more stable pain relief and improved sleep quality. Research questions The overall question in this thesis is whether long-acting opioids are more beneficial than short-acting ones in chronic non-malignant pain. This question is further broken down into three main research questions: 1. Are long-acting opioid formulations superior to short-acting ones in chronic pain? 2. How is mood state in CNMP patients affected by short-acting opioids? 3. How are opioids prescribed with reimbursement for chronic non-malignant pain in Norway, and is the prescription pattern in accordance with current guidelines? Methods In this thesis, four different research designs were applied to answer the main research question: I. A systematic review of the literature was performed to assess current evidence. EMBASE, Pubmed and Cochrane CENTRAL were searched for relevant trials. All trials comparing a long-acting with a short-acting formulation of the same opioid in equal daily dosages in chronic non-malignant pain were included in the analysis. II. A randomized, double blind, double dummy, clinical comparison of long- and short-acting dihydrocodeine for eight weeks was performed to add to the evidence base. Sixty patients suffering from chronic pain, who were taking codeineparacetamol for pain relief, were included. Pain intensity, stability in pain intensity, depression, quality of life and sleep quality were investigated. III. The change in mood state was investigated before and after administering codeineparacetamol tablets to the same participants as in the above-mentioned clinical trial. In the last week of participation in the randomized, double blind trial, mood state was also investigated before and after taking short-acting dihydrocodeine or placebo. IV. A pharmacoepidemiological trial was used to investigate the current prescription practice of opioids. Data were collected from the Norwegian prescription database, which contains data about all prescriptions that patients collected from pharmacies in Norway since 2004. The study population included all patients who received at least one analgesic reimbursed with the reimbursement code -71 (code for chronic pain) in 2009 and 2010. Data on all analgesics and potentially addictive comedications in these patients were analyzed. Results I. Long-acting opioid formulations did not provide improved analgesia compared to short-acting opioid formulations in any of the six randomized trials included in the systematic review. Stability of pain relief, physical function, quality of life and depression were not investigated in any of the trials. In three of the studies, the quality of sleep was evaluated, but no difference between groups was found in any of them. Adverse events were not investigated properly in any of the trials and addiction, tolerance and hyperalgesia were not addressed at all in any of the trials. II. No significant differences in pain intensity, stability in pain, quality of life, and sleep quality or depression were observed between the groups randomized to longand short-acting dihydrocodeine in the clinical trial. III. We found a significant rise in mood state in patients after taking short-acting codeine and short-acting dihydrocodeine, but not after taking a placebo. This rise in mood state was higher for patients experiencing a more dysphoric mood state at the end of the dosing intervals compared to those who had a less dysphoric mood state immediately before receiving the next opioid dose. IV. About 2 % of the Norwegian population received reimbursement for at least one analgesic in 2010, but only 0.14 % of the population received an opioid with reimbursement. Oxycodone was the most frequently prescribed opioid, followed by buprenorphine, tramadol, codeine, morphine and fentanyl. Of the 6875 patients who received at least one opioid reimbursement in 2010, 4047 of them used mainly long-acting opioids, 1051 used mainly short-acting opioids and 1346 used both formulations. In the two groups that received mainly long-acting and shortacting opioids, approximately 60 % received other opioids without reimbursement, approximately 40 % received benzodiazepines and 34 % and 47 % in the two groups, respectively, received benzodiazepine-like hypnotics. In the group that received both short- and long-acting opioids with reimbursement, 70 % received additional opioids without reimbursement, 51 % received benzodiazepines and 41 % received benzodiazepine-like hypnotics. Conclusions A. There is no available evidence to support the fact that long-acting opioid formulations are superior to short-acting formulations in CNMP. Both opioid formulations carry the risk of addiction, problematic opioid use and other side effects. Thus, guidelines should emphasize that opioids should be used rarely and only in selected patients. Physicians should not be led to believe that long-acting opioids are safer than shortacting ones. Easier dosage regimen and monitoring can still make long-acting formulations preferable over short-acting formulations in some CNMP patients. B. Many CNMP patients taking short-acting opioids suffer from a dysphoric mood state and experience a rise in mood after taking short-acting opioids. The change in mood state seen in CNMP patients has the same pattern as the change seen in opioidaddicted subjects receiving methadone. A rise in mood after taking opioids might be a relative contraindication to such treatment, while possibly increasing the risk of addiction and problematic opioid use. C. Few of the patients that use opioids for CNMP get their expenses reimbursed. Patients that use opioids without reimbursement should receive reimbursement to avoid unnecessary costs if they meet the criteria to receive it and the usage is in accordance with guidelines. If the usage is not in accordance with guidelines, they might benefit more from being weaned off of the opioids. Even though most CNMP patients use non-opioid analgesics, a high percentage of opioid users use both long- and shortacting formulations, in addition to other addictive substances, like benzodiazepines. This pattern of use is believed to carry a higher risk of addiction than using just one opioid alone.