Background and aims
Dextropropoxyphene (DXP) is a synthetic opioid that was prescribed worldwide for mild to moderate pain. It was withdrawn from the European market in 2009. In this study we aim to investigate the effect of the market withdrawal of dextropropoxyphene in Norway on overall use of opioids and other analgesics at an individual level.
Data were collected from the nationwide Norwegian Prescription Database (NorPD). It covers all prescription of drugs from 01 January 2004 from Norwegian pharmacies dispensed to individuals outside institutions. The study period was divided in two 2-year periods from 01 September 2008 to 31 August 2010, and from the market withdrawal of DXP on 01 September 2010 to 31 August 2012. We included every individual that filled at least one prescription of dextropropoxyphene in the first 2-year period in our study population. In this study dextropropoxyphene, codeine and tramadol are defined as “weak opioids”, and all other opioids are termed “strong opioids”.
Nine thousand one hundred and seventy-one individuals were included in our study population. Four thousand two hundred and ninety filled a prescription of DXP only once and were classified as “single users”, 2,990 were users with prescriptions of up to 200 defined daily doses (DDD) over the first 2-year period, or “sporadic users”, and 1,886 were classified high users with over 200 DDDs over a 2-year period. After the market withdrawal 8,392 continued to be prescribed analgesics or benzodiazepines. In the single user group, the proportion of users of weak opioids decreased from 69.5% to 57.6%, whereas the proportion of users of strong opioids was unchanged. Among the sporadic user group, the proportion of users of weak opioids went from 69.7% to 71.0%, the proportion using tramadol from 39.1% to 43.9%, and the users of strong opioids from 25.8% to 31.3%. In the high user group, there was an increase in the number of users of strong opioids from 37.8% to 51.4%. The amount of strong opioids prescribed in the high user group increased from a mean of 262.5 DDD to a mean of 398.3 DDD in the following 2 years. The amount of tramadol increased in all groups and was 3 times as high in the high user group after market withdrawal of DXP.
Our study showed that the withdrawal of DXP lead to an increase in prescription of other analgesics. The proportion of users increased in all three groups and so did the prescribed amount of other analgesics. Both the proportion of users of other opioids and the amount prescribed increased considerably. However, 1 in 10 earlier users of DXP stopped using prescribed analgesics altogether in the following 2 years. The increase in use among earlier high users of DXP was most striking.
This study documents markedly increased prescriptions of other opioids after withdrawal of dextropropoxyphene due to its high risk of serious complications. However, consequences of the increased use of opioids among earlier high users of DXP such as changes in risk of poisonings, accidental deaths and suicides remain to be investigated.
Research funding: None declared.
Conflict of interest: The authors have no conflict of interest to declare.
Informed consent: Not applicable, see below.
Ethical approval: The Norwegian Prescription Database (NorPD) is a nationwide database with its own regulations. The database contains data on an individual level, but in pseudonyms, so that information that can identify an individual will not be accessible. When the NorPD is not linked to any other data source, approval from the Regional Ethics Committee is not needed.
 Li Wan Po A, Zhang WY. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. Br Med J 1997;315:1565–71.10.1136/bmj.315.7122.1565Search in Google Scholar
 Association of Pharmaceutical Industry in Norway. The Norwegian Pharmaceutical Product Compendium 1982/1983.Search in Google Scholar
 Hayes CJ, Hudson TJ, Phillips MM, Bursac Z, Williams JS, Austin MA, Edlund MJ, Martin BC. The influence of propoxyphene withdrawal on opioid use in veterans. Pharmacoepidemiol Drug Saf 2015;24:1180–8.10.1002/pds.3851Search in Google Scholar PubMed
 Ray WA, Murray KT, Kawai V, Graham DJ, Cooper WO, Hall K, Stein CM. Propoxyphene and the risk of out-of-hospital death. Pharmacoepidemiol Drug Saf 2013;22:403–12.10.1002/pds.3411Search in Google Scholar PubMed
 Curtis JR, Xie F, Smith C, Saag KG, Chen L, Beukelman T, Mannion M, Yun H, Kertesz S. Changing trends in opioid use among patients with rheumatoid arthritis in the United States. Arthritis Rheumatol 2017;69:1733–40.10.1002/art.40152Search in Google Scholar PubMed
 Jonasson B, Jonasson U, Saldeen T. The manner of death among fatalities where dextropropoxyphene caused or contributed to death. Forensic Sci Int 1998;96:181–7.10.1016/S0379-0738(98)00123-6Search in Google Scholar PubMed
 Jonasson B, Jonasson U, Saldeen T. Suicides may be overreported and accidents underreported among fatalities due to dextropropoxyphene. J Forensic Sci 1999;44:334–8.10.1520/JFS14458JSearch in Google Scholar PubMed
 Hawton K, Simkin S, Gunnell D, Sutton L, Bennewith O, Turnbull P, Kapur N. A multicentre study of coproxamol poisoning suicides based on coroners’ records in England. Br J Clin Pharmacol 2005;59:207–12.10.1111/j.1365-2125.2004.02252.xSearch in Google Scholar PubMed PubMed Central
 Hawton K, Simkin S, Deeks J. Co-proxamol and suicide: a study of national mortality statistics and local non-fatal self poisonings. Br Med J 2003;326:1006–8.10.1136/bmj.326.7397.1006Search in Google Scholar PubMed PubMed Central
 Committee on the Safety of Medicines of the UK. Overdose risk prompts UK withdrawal of propoxyphene combination. J Pain Palliat Care Pharmacother 2006;20:49–50.10.1080/J354v20n04_09Search in Google Scholar PubMed
 Norwegian Medicines Agency, Annual Report of Adverse Effects 2009.Search in Google Scholar
 Food, U.S.D.O.H. Drug Administration Public Health Service, Human S. Food and Drug Administration recommends against the continued use of propoxyphene. J Pain Palliat Care Pharmacother 2011;25:80–2.10.3109/15360288.2010.549553Search in Google Scholar PubMed
 Hawton K, Bergen H, Simkin S, Brock A, Griffiths C, Romeri E, Smith KL, Kapur N, Gunnell D. Effect of withdrawal of co-proxamol on prescribing and deaths from drug poisoning in England and Wales: time series analysis. Br Med J 2009;338:b2270.10.1136/bmj.b2270Search in Google Scholar PubMed PubMed Central
 Hawton K, Bergen H, Waters K, Murphy E, Cooper J, Kapur N. Impact of withdrawal of the analgesic Co-proxamol on nonfatal self-poisoning in the UK. Crisis 2011;32:81–7.10.1027/0227-5910/a000063Search in Google Scholar PubMed
 Sandilands EA, Bateman DN. Co-proxamol withdrawal has reduced suicide from drugs in Scotland. Br J Clin Pharmacol 2008;66:290–3.10.1111/j.1365-2125.2008.03206.xSearch in Google Scholar PubMed PubMed Central
 Corcoran P, Reulbach U, Keeley HS, Perry IJ, Hawton K, Arensman E. Use of analgesics in intentional drug overdose presentations to hospital before and after the withdrawal of distalgesic from the Irish market. BMC Clin Pharmacol 2010;10:6.10.1186/1472-6904-10-6Search in Google Scholar PubMed PubMed Central
 Hawton K, Bergen H, Simkin S, Wells C, Kapur N, Gunnell D. Six-year follow-up of impact of co-proxamol withdrawal in England and Wales on prescribing and deaths: time-series study. PLoS Med 2012;9:e1001213.10.1371/journal.pmed.1001213Search in Google Scholar PubMed PubMed Central
 Becquemont L, Delespierre T, Bauduceau B, Benattar-Zibi L, Berrut G, Corruble E, Danchin N, Derumeaux G, Doucet J, Falissard B, Forette F, Hanon O, Pasquier F, Pinget M, Ourabah R, Bucher S, Lazkani A, Piedvache C, Bertin P. Consequences of dextropropoxyphene market withdrawal in elderly patients with chronic pain. Eur J Clin Pharmacol 2014;70:1237–42.10.1007/s00228-014-1722-xSearch in Google Scholar PubMed
 Gaubert S, Vie M, Damase-Michel C, Pathak A, Montastruc JL. Dextropropoxyphene withdrawal from a French university hospital: impact on analgesic drug consumption. Fundam Clin Pharmacol 2009;23:247–52.10.1111/j.1472-8206.2008.00661.xSearch in Google Scholar PubMed
 Aubrun F, Chretien E, Letrilliart L, Ginoux M, Belhassen M, Lanteri-Minet M, Van Ganse E, Beloeil H. What are the therapeutic alternatives to dextropropoxyphene in France? A prescribers’ survey. Anaesth Crit Care Pain Med 2017;36:15–9.10.1016/j.accpm.2016.01.007Search in Google Scholar PubMed
 Furu K. Establishment of the nationwide Norwegian Prescription Database (NorPD) – new opportunities for research in pharmacoepidemiology in Norway. Nor J Epidemiol 2008;18:129–36.Search in Google Scholar
 WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2018. Oslo, Norway, 2017.Search in Google Scholar
 Svendsen K, Borchgrevink P, Fredheim O, Hamunen K, Mellbye A, Dale O. 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. Palliat Med 2011;25:725–32.10.1177/0269216311398300Search in Google Scholar PubMed
 Skurtveit S, Sakshaug S, Hjellvik V, Berg C, Handal M. Bruk av vanedannende legemidler i Norge 2005–2013, Folkehelseinstituttet. Statistikk, 2014.Search in Google Scholar
 Birke H, Sjøgren P, Ekholm O, Fredheim O, Clausen T, Skurtveit S. Tramadol use in Norway: a register-based population study. Pharmacoepidemiol Drug Saf 2018. Doi: 10.1002/pds.4626 [Epub ahead of print].10.1002/pds.4626Search in Google Scholar PubMed
 Van Ganse E, Belhassen M, Ginoux M, Chretien E, Cornu C, Ecoffey C, Aubrun F. Use of analgesics in France, following dextropropoxyphene withdrawal. BMC Health Serv Res 2018;18:231.10.1186/s12913-018-3058-1Search in Google Scholar PubMed PubMed Central
 Bramness JG, Furu K, Skurtveit S, Engeland A. Effect of the market withdrawal of carisoprodol on use of other prescribed drugs with abuse potential. Clin Pharmacol Ther 2012;91:438–41.10.1038/clpt.2011.250Search in Google Scholar PubMed
 Ojanpera I, Kriikku P, Vuori E. Fatal toxicity index of medicinal drugs based on a comprehensive toxicology database. Int J Legal Med 2016;130:1209–16.10.1007/s00414-016-1358-8Search in Google Scholar PubMed
 Barkin RL, Barkin SJ, Barkin DS. Propoxyphene (dextropropoxyphene): a critical review of a weak opioid analgesic that should remain in antiquity. Am J Ther 2006;13: 534–42.10.1097/01.mjt.0000253850.86480.fbSearch in Google Scholar PubMed
 Pottegard A, Christensen R, Houji A, Christiansen CB, Paulsen MS, Thomsen JL, Hallas J. Primary non-adherence in general practice: a Danish register study. Eur J Clin Pharmacol 2014;70:757–63.10.1007/s00228-014-1677-ySearch in Google Scholar PubMed
©2018 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.