O. M. S. Fredheim

Clinical pharmacology of methadone for pain.

Background: This topical review addresses methadones pharmacology, its application in malignant and non‐malignant pain conditions, practical issues related to methadone for the treatment of pain and its influence on QTc time.

Choosing the unit of measurement counts: the use of oral morphine equivalents in studies of opioid consumption is a useful addition to defined daily doses.

Aim: Defined daily dose (DDD) is the most common measurement unit used in drug consumption studies. The DDD for opioids may not reflect their relative clinical potencies. The aim of this study was to explore whether opioid consumption data may be interpreted differently when adding oral morphine equivalent (OMEQ) dose as a measurement unit compared with using DDD. Methods: The equianalgesic ratio of each opioid relative to morphine was tabulated. Data on opioid consumption expressed in DDD were converted to OMEQs using the equianalgesic ratios. The opioid consumption was compared in three different study settings: clinical data from an opioid switching study, trends within one country and a comparison between countries. Results: Using DDD, the opioid consumption in Norway between 2004–2008 increased of 6.7%, while the increase was 23.6% using OMEQ. While DDD/1000 inhabitants/day showed that Sweden had the highest consumption of opioids among the Nordic countries, OMEQ/1000 inhabitants/day showed that Denmark had the highest consumption. In the switching study DDD indicated a reduction in analgesic dosing and OMEQ an increase when switching from WHO step II to III. Conclusion: OMEQ reflects clinical dosing better than DDD, and can give additional insight into opioid consumption when combined with DDD. Using OMEQ can also lead to different conclusions in opioid consumption studies compared with using DDD alone.

Prescription pattern of codeine for non‐malignant pain: a pharmacoepidemiological study from the Norwegian Prescription Database

Background: Opioid prescription for pain relief is increasing. Codeine is the dominating opioid in several European countries, with Norway being among the highest codeine users.

Concomitant medication among persistent opioid users with chronic non-malignant pain

Recent guidelines for opioid treatment of chronic non‐malignant pain discourage co‐medication with benzodiazepines and benzodiazepine‐related hypnotics, whereas co‐medication with non‐opioid analgesics and co‐analgesics may offer a beneficial opioid sparing effect, and is recommended. The aim of this study was to describe 1‐year periodic prevalence of co‐medication with benzodiazepines, benzodiazepine‐related hypnotics, non‐opioid analgesics, co‐analgesics and antidepressants in persistent opioid users with chronic non‐malignant pain.

Differential patterns of opioid use : Defining persistent opioid use in a prescription database.

The aim of this study was to develop definitions to identify persons with clinically different patterns of persistent opioid use based on data from prescription databases.

Low-dose transdermal buprenorphine – long-term use and co-medication with other potentially addictive drugs

Recently, low‐dose transdermal buprenorphine (LD‐TD‐BUP) was introduced for treatment of patients with chronic non‐malignant pain. The primary aim of this study was to determine the proportion of patients who were prescribed LD‐TD‐BUP for non‐malignant pain who became long‐term users. The secondary aim was to determine the proportion of patients who co‐medicated with other opioids or benzodiazepines during treatment with LD‐TD‐BUP.

Increasing use of opioids for pain

In this issue you will find a paper by Zin et al. entitled ‘Changing Patterns and Trends of Strong Opioid Prescribing in Primary Care’ (Zin et al., 2014). Zin et al. have investigated the prescription trends in the UK for four commonly prescribed strong opioids: morphine, oxycodone, fentanyl and buprenorphine. Prescription codes are used to stratify the patients as cancer or non-cancer patients. The overall pattern is that during 10 years there has been a large increase both in the number of patients receiving opioid therapy and in the number of prescriptions per patient. This pattern is observed for both cancer pain and non-cancer pain. The increasing use of opioids for cancer pain indicates that a higher number of patients receive potent analgesic therapy and that therapy is probably being started earlier in the disease trajectory. This development is likely to be an indication of improved treatment of cancer pain and should thus be welcomed. Increasing prevalence of prescriptions of low doses of opioids is probably at least partially due to increasing use of opioids for acute pain conditions. This finding is also probably a sign of improved pain treatment. Even though this development should probably be welcomed, it is important for clinicians to re-evaluate the indication for opioid treatment if the acute pain condition has not resolved within 2 to 3 weeks. The increase in high-dose treatment for nonmalignant pain is probably due to the increased use of opioids for chronic non-malignant pain. This finding confirms trends from other countries, but raises several concerns. Even though opioid therapy has been reported to improve pain in clinical trials, such trials might not reflect the clinical realities. Particularly, factors like patient selection and short duration of follow-up make it necessary to question the clinical validity of the published clinical trials. On the other hand, pharmacoepidemiological studies have demonstrated that many patients receiving opioids for chronic non-malignant pain receive increasing doses, receive short-acting opioids, combine different opioids and formulations, and co-medicate with other drugs with addictive properties such as benzodiazepines and benzodiazepine-related hypnotics (Fredheim et al., 2010; Mellbye et al., 2012). Pharmacoepidemiological studies based on prescription data have, until recent years, been based primarily on either small samples or non-representative study populations like persons in insurance databases. A major step forward has been the creation of nationwide prescription databases and databases covering large and representative samples of the population. These databases have allowed research with different designs and methodologies: • cross sectional studies have made it possible to stratify patients with regard to opioid doses and investigate patterns of co-medication • longitudinal studies have made it possible to follow patients over time with regard to duration of treatment, changes in drug doses and risk of problematic opioid use • linkage studies where data from other registries are linked to either cross sectional or longitudinal data on drug use have made it possible to investigate the relationship between sociodemographic and medical characteristics and drug use The use of prescription databases eliminates important biases related to recall bias in studies based on self-reported drug use, and allows for more detailed analyses compared with studies of wholesale data. However, there are some important weaknesses in pharmacoepidemiological studies such as the study by Zin et al. The major weakness is that it is not known whether the prescribed drugs are actually dispensed to the patients or whether they are used by the patients and used as prescribed. If the aim of the study is to investigate which drugs patients use, not what doctors prescribe, the validity is probably higher if studies are based not on prescriptions in physicians’ records but on data on drugs that have actually been dispensed to patients. A further challenge is that with little knowledge of the patients’ sociodemographic and medical characteristics it is not possible to draw robust conclusions regarding whether the observed prescription patterns are appropriate or not.

433 MONITORING THE OPIOID CONSUMPTION: MORPHINE-EQUIVALENT DEFINED DAILY DOSE AS A SUPPLEMENT TO DDD

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