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Joint Bone Spine 76 (2009) 449–451

Editorial

The dextropropoxyphene controversy

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eywords: Analgesics; Dextropropoxyphene; Coproxamol; Marketing withdra

Dextropropoxyphene is a weak opioid that was first intro-uced half a century ago as an analgesic in the USA.extropropoxyphene combined with acetaminophen, or coprox-

mol, rapidly became the most widely prescribed analgesichroughout the world [1,2]. However, dextropropoxyphene lostts marketing license in Switzerland in 2003, in Sweden in005, and in the UK in 2007. The European Medicines AgencyEMEA) has started a referral procedure that may lead to theithdrawal of the marketing license for dextropropoxyphene

hroughout the European Union. What explains the sudden fallnto disgrace of this hugely popular drug that is valued world-ide for its strong safety record [1,3,4]?

. Doubts about efficacy

Dextropropoxyphene is a weak opioid that is chemically sim-lar to methadone and acts as an agonist of the � receptors1]. Until 2001, dextropropoxyphene was available in Frances the hydrochloride salt in a single-drug preparation containing5 mg per tablet (Antalvic®). The license was held at the timey Hoechst-Houdé Inc., who discontinued the drug, a decisionhat was met with indifference by the public and professionalslike.

Doubts about the efficacy of dextropropoxyphene comeainly from studies in patients with acute postoperative pain,

sed as a model of acute pain. Dextropropoxyphene hydrochlo-ide 65 mg and its close relative dextropropoxyphene napsylate00 mg exhibited only modest effects, comparable to thosef 500 mg of acetaminophen, 50 mg of tramadol, or 60 mg ofodeine; and far smaller than those of 400 mg of ibuprofen or0 mg of diclofenac [5]. Unfortunately, there are no random-zed controlled trials of the efficacy of dextropropoxyphenen chronic pain [6]. However, a brief (2-week) trial suggestshat dextropropoxyphene napsylate (300 mg/d) may be as effec-ive as tramadol (300 mg/d) in patients with pain from knee or

ip osteoarthritis and may be associated with a lower rate ofreatment discontinuations related to adverse events (11% vs6%) [6]. However, this study has serious methodological weak-esses, including absence of a placebo arm, and consequently

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ts results cannot be used to draw conclusions about the role forextropropoxyphene in the management of osteoarthritis [6].urthermore, dextropropoxyphene as a single-drug preparationas fallen into disuse.

Coproxamol, in contrast, is extremely popular among patientsnd physicians. However, studies of coproxamol found no prooff greater efficacy compared to acetaminophen alone [4]. Inatients with acute postoperative pain, oral administration of5 mg of dextropropoxyphene hydrochloride with 650 mg ofcetaminophen had the same effect as 100 mg of oral tramadolr 1 g of oral acetaminophen and a far smaller effect than oralonsteroidal anti-inflammatory drugs (NSAIDs) [5]. The effectsf the single doses used in most clinical trials may fail to reflecthe effects of long-term coproxamol therapy [7], as suggestedy pharmacokinetic data [8]. The mean plasma eliminationalf-life of dextropropoxyphene and its active metabolite nor-ropoxyphene is 22 hours in young adults and 37–42 hours inlder individuals, so that accumulation occurs with repeated-ose therapy, possibly potentiating the analgesic effect [7,8].n a double-blind trial, most patients on long-term coproxamolherapy for joint disease felt that the drug was more effec-ive than acetaminophen alone [9]. Nevertheless, the efficacyf coproxamol will remain in doubt until studies establish itsuperiority over acetaminophen in patients with chronic pain,ncluding patients with pain from osteoarthritis. The uncer-ainty regarding the analgesic efficacy of coproxamol applieso all currently marketed combination tablets of acetaminophennd dextropropoxyphene. The coproxamol preparation availablen France (Di-Antalvic®) contains 400 mg of acetaminophennd 30 mg of dextropropoxyphene hydrochloride, compared to25 mg and 32.5 mg, respectively, in the preparation availablen the UK. Another preparation (Propofan®) contains 400 mg ofcetaminophen, 27 mg of dextropropoxyphene hydrochloride,nd 30 mg of caffeine.

. A strong safety record

Serum alkaline phosphatase elevation is common duringoproxamol treatment; and cholestatic or mixed hepatitis is a

by Elsevier Masson SAS. All rights reserved.

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50 Editorial / Joint Bone

ell-known, although usually asymptomatic, adverse effect ofextropropoxyphene [10]. Hypoglycemia is far less commonnd occurs chiefly in the very elderly and in patients with renalailure [11,12]. Notwithstanding these adverse effects, clinicalxperience suggests that the greatest quality of coproxamol isrobably an excellent safety profile. This opinion is supportedy the results of a randomized double-blind trial comparingcetaminophen plus dextropropoxyphene to acetaminophen plusodeine for 1 week in 141 patients [3]. Adverse events requiringtudy withdrawal were three times more common with codeine27/71, 38%) than with dextropropoxyphene (9/70, 13%). Whensed in standard dosages, coproxamol is associated with fairlyow rates of nausea, vomiting, constipation, drowsiness, andizziness, which are the main reasons for discontinuing opioidherapy [3,6].

The gastrointestinal and neuropsychological side effects ofpioids can be expected to mirror their analgesic effects, as bothre related to � receptor stimulation. Therefore, the good safetyrofile of coproxamol may merely reflect its limited efficacy6]. None of the available coproxamol preparations containshe dosages corresponding to a step 2 analgesic, according tohe recommendations on cancer pain treatment issued by the

orld Health Organization [13]. To be more effective than stepdrugs,i.e., acetaminophen or an NSAID, acetaminophen 500g should be combined with 50-100 mg of dextropropoxyphene

13].

. Yet, coproxamol can kill

In the 1970s and 1980s, reports of large numbers of deathsaused by coproxamol overdosage were a matter of great con-ern to health care authorities, particularly in the UK, Canada,he US, Australia and the Scandinavian countries [1,2]. A retro-pective review of suicide deaths recorded in England and Walesndicated that coproxamol alone caused 255 deaths per year95% confidence interval [95% CI]: 238–274) in 1997–1999,ompared to 309 (95% CI: 289–330) for tricyclic antidepres-ants and 123 (95% CI: 110–136) for acetaminophen [14]. Theelative risk (RR) of death was higher with coproxamol thanith imipramine antidepressants (RR: 2.3; 95% CI: 2.1–2.5) or

cetaminophen (RR: 28.1; 95% CI: 24.9–32.9) [14]. A surveyonducted in Scotland over the 2-year period from July 2000o June 2002 showed that coproxamol overdosage caused 24.6eaths/106 prescriptions (95% CI: 19.7–30.4) compared to twoeaths (0.88–4) for combinations of acetaminophen (500 mg)nd codeine (8, 15, or 30 mg) and 2.4 deaths (0.5–7.2) for com-inations of acetaminophen (500 mg) and dihydrocodeine (10 or0 mg), although the incidence of self-poisoning was similar forhe three categories of analgesics [15]. An earlier study found alose association between the amount of coproxamol deliveredy prescription and the number of deaths by overdosage in Northmerica and Northern Europe [2].Because coproxamol is rapidly absorbed by the intes-

ine, lethal plasma levels of dextropropoxyphene and nor-ropoxyphene may be reached rapidly after ingestion [1]. Theean time from ingestion to death is about 5 hours, and 80

o 90% of deaths from dextropropoxyphene overdosage occur

e 76 (2009) 449–451

efore hospital admission [2]. The first cause of death is centralervous system depression, which causes impaired conscious-ess and hypoventilation. These effects are typical of opioidsnd can be reversed by injecting a � receptor antagonist such asaloxone, although they are often potentiated by the concomitantngestion of alcohol or psychoactive drugs such as benzodi-zepines [1,2,15]. Dextropropoxyphene and, to an even greateregree, norpropoxyphene impair heart function, probably bynterfering with the sodium and potassium channels. This effect,hich is not reversed by naloxone, may lead to decreased con-

ractility, asystole, bradycardia, QRS prolongation, and QTcrolongation [1,15,16].

. Should coproxamol be banned?

Mounting a defense against such damning charges may seemnrealistic. Here is a drug that has earned a reputation ofeing dangerous yet fails to induce greater relief of acute painhan acetaminophen and, despite its long-standing popularity,emains untested in chronic pain, its indication of choice. Theithdrawal of coproxamol in the UK (which was gradual, toive physicians time to find alternative treatments) was asso-iated with a decrease in the number of self-poisoning deaths,espite the use of other analgesics as substitutes [17].

Nevertheless, coproxamol still has strong advocates. Someatients fail to find acceptable alternatives [18,19]. The over-helming majority of general practitioners and rheumatologists

n the UK want the drug to stay on the market [18]. They arguehat coproxamol is the only satisfactory analgesic for someatients with chronic pain, who use it appropriately and haveo suicidal tendencies. Depriving such patients of coproxamolay be considered unethical [19]. An additional argument in

avor of keeping coproxamol in France comes from a reporty the Poison Control Center: of 12,444 coproxamol overdosesecorded between 1995 and 2003, only 62 were fatal, yielding aean of seven deaths per year [20]. This result may be ascrib-

ble to the low level of use of analgesics for suicide in France20]. If coproxamol is not dangerous in our country, why removet from our pharmacopoeia, given its considerable usefulness inome patients?

It is to be hoped that the decision taken by the EMEA willake local considerations into account instead of instituting a banor the entire European Union. A useful approach would be tosk the health care authorities of countries where coproxamolemains available to conduct clinical trials versus acetaminophenn patients with chronic pain.

onflicts of interests

The author declares no conflict of interest.

eferences

[1] Young RJ. Dextropropoxyphene overdosage. Pharmacological considera-tions and clinical management. Drugs 1983;26:70–9.

[2] Simkin S, Hawton K, Sutton L, et al. Coproxamol and suicide: preventingthe continuing toll of overdose deaths. Q J Med 2005;98:159–70.

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Editorial / Joint Bone

[3] Boissier C, Perpoint B, Laporte-Simitsidis S, et al. Acceptability andefficacy of two associations of paracetamol with a central analgesic (dextro-propoxyphene or codeine): comparison in osteoarthritis. J Clin Pharmacol1992;32:990–5.

[4] Li Wan Po A, Zhang WY. Systematic overview of coproxamol to assessanalgesic effects of addition of dextropropoxyphene to paracetamol. BMJ1997;315:1565–71.

[5] McQuay H, Moore A. Acute pain: conclusion. In: McQuay H, MooreA, editors. An evidence-based resource for pain relief. Oxford: OxfordUniversity Press; 1998. p. 187–92.

[6] Bannwarth B. Risk–benefit assessment of opioids in chronic noncancerpain. Drug Saf 1999;21:283–96.

[7] Hanks GW, Forbes K. Coproxamol is effective in chronic pain. BMJ1998;316:1980 [letter].

[8] Flanagan RJ, Johnston A, White AS, et al. Pharmacokinetics of dextro-propoxyphene and nordextropropoxyphene in young and elderly volunteersafter single and mutiple dextropropoxyphene dosage. Br J Clin Pharmacol1989;28:463–9.

[9] Owen M, Hills LJ. How safe is dextropropoxyphene? Med J Aust1980;1:617–8.

10] Bergeron L, Guy C, Ratrema M, et al. Dextropropoxyphène et atteinteshépatiques: à propos de 4 cas et revue de la littérature. Thérapie2002;57:464–72.

11] Blaison G, Bloch JG, Calvel L, et al. Hypoglycémies induites parl’association de dextropropoxyphène chlorhydrate-paracétamol. Sem HopParis 1991;67:1964–6.

12] Soubrier M, Prudat M, Marcaggi X, et al. Hypoglycémies sous dextro-propoxyphène chez des grands vieillards. Sept observations. Presse Med

1991;20:1628.

13] World Health Organization. Cancer pain relief. Geneva: WHO; 1986.14] Hawton K, Simkin S, Deeks J. Coproxamol and suicide: a study of

a national mortality statistics and local nonfatal self-poisonings. BMJ2003;326:1006–8.

76 (2009) 449–451 451

15] Afshari R, Good AM, Maxwell SR, et al. Coproxamol overdose is asso-ciated wih a 10-fold excess mortality compared with other paracetamolcombination analgesics. Br J Clin Pharmacol 2005;60:444–7.

16] Ulens C, Daenens P, Tytgat J. Norpropoxyphene-induced cardiotoxicity isassociated with changes in ion selectivity and gating of HERG currents.Cardiovasc Res 1999;44:568–78.

17] Sandilands EA, Bateman DN. Coproxamol withdrawal has reducedsuicide from drugs in Scotland. Br J Clin Pharmacol 2008;62:290–3.

18] Coombes R. Is killing pain worth the risk? BMJ 2007;334:186–7.19] Ottewell L, Walker DJ. Coproxamol: where have all the patients gone?

Rheumatology 2008;47:375.20] Afssaps. Point d’information sur l’association paracétamol et dextro-

propoxyphène à la suite de l’évaluation par les centres antipoison.Communiqué de presse du 28 juillet 2005.

Bernard Bannwarth a,∗,b

Christophe Richez a

a Service de rhumatologie, groupe hospitalier Pellegrin, placeAmélie-Raba-Léon, 33076 Bordeaux cedex, France

Laboratoire de thérapeutique, université Victor-Ségalen, 146,rue Léo-Saignat, 33076 Bordeaux cedex, France

∗ Corresponding author.E-mail address: bernard.bannwarth@u-bordeaux2.fr

2 April 2009

Available online 14 July 2009