dextropropoxyphene

Dextropropoxyphene is generally considered a weak analgesic, with several studies finding its efficacy is no better than acetaminophen.

Like codeine, it is a weak opioid. However, dextropropoxyphene has one-third to one-half of the analgesic activity of codeine.{{cite journal | vauthors = Barkin RL, Barkin SJ, Barkin DS | title = Propoxyphene (dextropropoxyphene): a critical review of a weak opioid analgesic that should remain in antiquity | journal = American Journal of Therapeutics | volume = 13 | issue = 6 | pages = 534–542 | date = 2006 | pmid = 17122535 | doi = 10.1097/01.mjt.0000253850.86480.fb }}

Dextropropoxyphene has been found to be helpful in relieving the symptoms of restless legs syndrome.{{cite web|url=http://www.answers.com/topic/restless-legs-syndrome |title=Restless legs syndrome: Definition from |publisher=Answers.com |access-date=2009-08-19}}{{cite web|url=http://www.sleepmedicinecenters.com/Home/SleepDisorders/RestlessLegsSyndrome |title=Restless Leg Syndrome | work = Sleep Medicine Centers of WNY |publisher=Sleepmedicinecenters.com |access-date=2009-08-19}}{{cite web |url=http://www.rls.org/Document.Doc?&id=3 |work=Restless Leg Syndrome Foundation |title=Causes, diagnosis and treatment for the patient living with Restless Legs Syndrome (RLS) |date=1 April 2006 |access-date=2009-08-19 |archive-url=https://web.archive.org/web/20090902202608/http://www.rls.org/Document.Doc?&id=3 |archive-date=2 September 2009 |url-status=dead }}

Dextropropoxyphene is contraindicated in patients allergic to paracetamol (acetaminophen) or dextropropoxyphene, and in alcoholics. It is not intended for use in patients who are prone to suicide, anxiety, panic, or addiction.

Severe toxicity can occur with small increments above the therapeutic dose including cardiotoxicity, and fatal overdoses. This is especially true when the drug is combined with alcohol.{{cite journal | vauthors = Hayes CJ, Hudson TJ, Phillips MM, Bursac Z, Williams JS, Austin MA, Edlund MJ, Martin BC | title = The influence of propoxyphene withdrawal on opioid use in veterans | journal = Pharmacoepidemiology and Drug Safety | volume = 24 | issue = 11 | pages = 1180–1188 | date = November 2015 | pmid = 26248742 | pmc = 5305002 | doi = 10.1002/pds.3851 }}

Other side effects include:{{cite web | url=https://www.drugs.com/sfx/propoxyphene-side-effects.html | title=Propoxyphene Side Effects: Common, Severe, Long Term }}

• Constipation
• Itching
• Drowsiness
• Nausea
• Sensorineural deafness

Image:propoxyphene.jpg

Image:propoxyphene2.jpg

Dextropropoxyphene acts as a mu-opioid receptor agonist. It also acts as a potent, noncompetitive α₃β₄ neuronal nicotinic acetylcholine receptor antagonist,{{cite journal | url = http://jpet.aspetjournals.org/content/299/1/366.abstract | title = Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs — JPET | journal = Journal of Pharmacology and Experimental Therapeutics | date = October 2001 | volume = 299 | issue = 1 | pages = 366–371 | vauthors = Xiao Y | doi = 10.1016/S0022-3565(24)29338-1 }} as well as a weak serotonin reuptake inhibitor.

Overdose is commonly broken into two categories - liver toxicity (from paracetamol poisoning) and dextropropoxyphene overdose.

An overdose of dextropropoxyphene may lead to various systemic effects. Excessive opioid receptor stimulation is responsible for the CNS depression, respiratory depression, aspiration pneumonia, miosis, and gastrointestinal effects seen in propoxyphene poisoning. It may also account for mood- or thought-altering effects. In the presence of amphetamine, propoxyphene overdose increases CNS stimulation and may cause fatal convulsive seizures.{{Cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017078s048lbl.pdf|title=Dexedrine® (dextroamphetamine sulfate) Spansule® sustained release capsules [Label]|website=US Food and Drug Administration|publisher=Amedra Pharmaceuticals LLC|date=February 2015|access-date=November 11, 2016|quote=In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.}}

In addition, both propoxyphene and its metabolite norpropoxyphene have local anesthetic effects at concentrations about 10 times those necessary for opioid effects. Norpropoxyphene is a more potent local anesthetic than propoxyphene, and they are both more potent than lidocaine.{{cite journal | vauthors = Nickander RC, Emmerson JL, Hynes MD, Steinberg MI, Sullivan HR | title = Pharmacologic and toxic effects in animals of dextropropoxyphene and its major metabolite norpropoxyphene: a review | journal = Human Toxicology | volume = 3 | issue = Suppl | pages = 13S–36S | date = August 1984 | pmid = 6090306 | doi = 10.1177/096032718400300103 | s2cid = 1333582 }} Local anesthetic activity appears to be responsible for the arrhythmias and cardiovascular depression seen in propoxyphene poisoning.

Both propoxyphene and norpropoxyphene are potent blockers of cardiac membrane sodium channels, and are more potent than lidocaine, quinidine, and procainamide in this respect.{{cite journal | vauthors = Holland DR, Steinberg MI | title = Electrophysiologic properties of propoxyphene and norpropoxyphene in canine cardiac conducting tissues in vitro and in vivo | journal = Toxicology and Applied Pharmacology | volume = 47 | issue = 1 | pages = 123–33 | date = January 1979 | pmid = 425111 | doi = 10.1016/0041-008x(79)90079-6 | bibcode = 1979ToxAP..47..123H }} As a result, propoxyphene and norpropoxyphene appear to have the characteristics of a Vaughn-Williams Class Ic antiarrhythmic.

These direct cardiac effects include decreased heart rate (i.e. cardiovascular depression), decreased contractility, and decreased electrical conductivity (i.e., increased PR, AH, HV, and QRS intervals). These effects appear to be due to their local anesthetic activity and are not reversed by naloxone.{{cite journal | vauthors = Strøm J, Häggmark S, Madsen PS, Reiz S, Sørensen MB | title = Cardiac pacing and central hemodynamics in experimental propoxyphene induced shock | journal = Journal of Toxicology. Clinical Toxicology | volume = 23 | issue = 4–6 | pages = 353–6 | date = 1985 | pmid = 4057325 | doi = 10.3109/15563658508990644 }}{{cite journal | vauthors = Bredgaard Sørensen M, Strøm J, Sloth Madsen P, Angelo HR, Reiz S | title = Haemodynamic, electrocardiographic and cardiometabolic changes after overdose of propoxyphene. An experimental study in pentobarbitone-anaesthetized pigs | journal = Human Toxicology | volume = 3 | issue = Suppl | pages = 53S–59S | date = August 1984 | pmid = 6480018 | doi = 10.1177/096032718400300107 | s2cid = 2890957 }} Widening of the QRS complex appears to be a result of a quinidine-like effect of propoxyphene, and sodium bicarbonate therapy appears to have a positive direct effect on the QRS dysrhythmia.{{cite journal | vauthors = Stork CM, Redd JT, Fine K, Hoffman RS | title = Propoxyphene-induced wide QRS complex dysrhythmia responsive to sodium bicarbonate--a case report | journal = Journal of Toxicology. Clinical Toxicology | volume = 33 | issue = 2 | pages = 179–83 | date = 1995 | pmid = 7897759 | doi = 10.3109/15563659509000470 }}

Seizures may result from either opioid or local anesthetic effects. Pulmonary edema may result from direct pulmonary toxicity, neurogenic/anoxic effects, or cardiovascular depression.

Balance disorder is possible, with risk of falls from standing height.

Propoxyphene was initially introduced as propoxyphene hydrochloride. Shortly before the patent on propoxyphene expired, propoxyphene napsylate form was introduced to the market. The napsylate salt (the salt of naphthalene-2-sulfonic acid) is claimed to be less prone to non-medical use, because it is almost insoluble in water, so cannot be used for injection. Napsylate also gives lower peak blood level.{{cite book|isbn=978-0-7817-3481-3 |title=Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry|publisher=Lippincott Williams & Wilkins| vauthors = Wilson CO, Gisvold JH |year=2004}} Because of different molar mass, a dose of 100 mg of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg of propoxyphene hydrochloride.

Before the FDA-directed recall, dextropropoxyphene HCl was available in the United States as a prescription formulation with paracetamol (acetaminophen) in ratio from 30 mg / 600 mg to 100 mg / 650 mg (or 100 mg / 325 mg in the case of Balacet), respectively. These are usually named Darvocet. Darvon is a pure propoxyphene preparation that does not contain paracetamol.

In Australia, dextropropoxyphene is available on prescription, both as a combined product (32.5 mg dextropropoxyphene per 325 mg paracetamol branded as Di-gesic, Capadex, or Paradex; it is also available in pure form (100 mg capsules) known as Doloxene, however its use has been restricted.

Detectable levels of propoxyphene/dextropropoxyphene may stay in a person's system for up to 9 days after last dose and can be tested for specifically in nonstandard urinalysis, but may remain in the body longer in minuscule amounts.{{cite journal | vauthors = Kamal-Bahl SJ, Stuart BC, Beers MH | title = Propoxyphene use and risk for hip fractures in older adults | journal = The American Journal of Geriatric Pharmacotherapy | volume = 4 | issue = 3 | pages = 219–226 | date = September 2006 | pmid = 17062322 | doi = 10.1016/j.amjopharm.2006.09.005 }} Propoxyphene does not show up on standard opiate/opioid tests because it is not chemically related to opiates as part of the OPI or OPI 2000 panels, which detect morphine and related compounds. It is most closely related to methadone.{{cite journal | vauthors = Hayes CJ, Hudson TJ, Phillips MM, Bursac Z, Williams JS, Austin MA, Edlund MJ, Martin BC | title = The influence of propoxyphene withdrawal on opioid use in veterans | journal = Pharmacoepidemiology and Drug Safety | volume = 24 | issue = 11 | pages = 1180–1188 | date = November 2015 | pmid = 26248742 | pmc = 5305002 | doi = 10.1002/pds.3851 }}

Dextropropoxyphene was successfully tested in 1954 as part of US Navy and CIA-funded research on nonaddictive substitutes for codeine.{{cite web|title=Memorandum for the U.S. Secretary of Defense | date = 20 December 1977|url=http://www.esd.whs.mil/Portals/54/Documents/FOID/Reading%20Room/NCB/02-A-0846_RELEASE.pdf|url-status=live|archive-url=https://web.archive.org/web/20170916010918/http://www.esd.whs.mil/Portals/54/Documents/FOID/Reading%20Room/NCB/02-A-0846_RELEASE.pdf|archive-date=2017-09-16|access-date=2013-07-28}}

Without the propionyl group on the oxygen, the non-esterified alcohol precursor of propoxyphene (both enantiomers, known as darvon alcohol and novrad alcohol) have been employed as stoichiometric chiral reagents for asymmetric carbonyl reduction reactions involving aluminium hydride reagents.{{Cite journal | vauthors = Erickson TJ |date=1986-03-01 |title=Asymmetric synthesis of Darvon alcohol |journal=The Journal of Organic Chemistry |volume=51 |issue=6 |pages=934–935 |doi=10.1021/jo00356a034 |issn=0022-3263}}{{Cite book |title=Reductions in Organic Synthesis: Recent Advances and Practical Applications |chapter=Sixty Years of Hydride Reductions |date=1996-08-13 |publisher=American Chemical Society |isbn=978-0-8412-3381-2 | veditors = Abdel-Magid AF |series=ACS Symposium Series |volume=641 |location=Washington, DC |language=en |doi=10.1021/bk-1996-0641.ch001 | vauthors = Brown HC, Ramachandran PV |pages=1–30 }}

Dextropropoxyphene is subject to some controversy; while many physicians prescribe it for a wide range of mildly to moderately painful symptoms, as well as for treatment of diarrhea, many others refuse to prescribe it, citing limited effectiveness. In addition, the therapeutic index of dextroproxyphene is relatively narrow.

Caution should be used when administering dextropropoxyphene, particularly with children and the elderly and with patients who may be pregnant or breastfeeding; other reported problems include kidney, liver, or respiratory disorders, and prolonged use. Attention should be paid to concomitant use with tranquillizers, antidepressants, or excess alcohol.

Darvon, a dextropropoxyphene formulation made by Eli Lilly, which had been on the market for 25 years, came under heavy fire in 1978 by consumer groups that said it was associated with suicide. Darvon was never withdrawn from the market, until recently, but Lilly has waged a sweeping, and largely successful, campaign{{Citation needed|date=August 2009}} among doctors, pharmacists, and Darvon users to defend the drug as safe when it is used in proper doses and not mixed with alcohol. After determining the risks outweigh the benefits, the USFDA requested physicians stop prescribing the drug. On November 19, 2010, the FDA announced that Xanodyne Pharmaceuticals agreed to withdraw Darvon and Darvocet in the United States, followed by manufacturers of dextropropoxyphene.{{cite web | url = http://www.cnn.com/2010/HEALTH/11/19/fda.removes.drug/ | title = FDA pulls common pain med off the market | date = 19 November 2010 | work = CNN }}{{Cite web|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm234389.htm |title=Safety Alerts for Human Medical Products - Propoxyphene: Withdrawal - Risk of Cardiac Toxicity |date=November 19, 2010|website=www.fda.gov|publisher=US Food and Drug Administration|language=en|access-date=November 11, 2016}}

In Australia, both pure dextropropoxyphene capsules (as napsylate, 100 mg), marketed as Doloxene, and combination tablets and capsules (with paracetamol) all containing 32.5 mg dextropropoxyphene HCl with 325 mg paracetamol, which are currently available on prescription were supposed to be withdrawn from 1 March 2012,{{cite web | url = http://www.tga.gov.au/newsroom/media-2011-dextropropoxyphene-111122.htm | title = TGA to cancel four prescription pain-killers from 1 March 2012 | work = Therapeutic Goods Administration (TGA) | publisher = Commwealth of Australia | access-date = 29 November 2011 | archive-date = 4 December 2011 | archive-url = https://web.archive.org/web/20111204125631/http://www.tga.gov.au/newsroom/media-2011-dextropropoxyphene-111122.htm | url-status = dead }} but Aspen Pharma sought a review in the Administrative Appeals Tribunal which ruled in 2013 that the drugs could be sold under strict conditions.

On December 1, 2010, Health Canada and Paladin Labs Inc. announced the voluntary recall and withdrawal of Darvon-N from the Canadian market and the discontinuation of sale of Darvon-N.{{cite web | url = http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/public/_2010/darvon-n_pc-cp-eng.php | work = Health Canada | title = Darvon-N (dextropopoxyphene) - Recall and Withdrawal in Canada | date = 9 December 2002 }}

In November 2007, the European Commission requested the European Medicines Agency (EMA) to review the safety and effectiveness of dextropropoxyphene based medicines and on 25 June 2009 the EMA recommended a gradual withdrawal throughout the European Union. The EMA's conclusion was based on evidence that dextropropoxyphene-containing medicines were weak painkillers, the combination of dextropropoxyphene and paracetamol was no more effective than paracetamol on its own, and the difference between the dose needed for treatment and a harmful dose (the "therapeutic index") was too small.{{cite web

| url=http://www.emea.europa.eu/pdfs/human/referral/dextropropoxyphene/40106109en.pdf

| title=Questions and answers on the withdrawal of the marketing authorisations for medicines containing dextropropoxyphene

| date=25 June 2009

| publisher=European Medicines Agency

| access-date=2009-09-08

| archive-url=https://web.archive.org/web/20090902075020/http://www.emea.europa.eu/pdfs/human/referral/dextropropoxyphene/40106109en.pdf

| archive-date=2 September 2009

| url-status=dead

}}

In February 2010, Medsafe announced Paradex and Capadex (forms of dextropropoxyphene) were being withdrawn from the marketplace due to health issues, and withdrawal in other countries.

{{cite web

| url=http://www.scoop.co.nz/stories/GE1002/S00034.htm

| title=Paradex And Capadex To Be Withdrawn From NZ

| access-date=2010-02-21

}}

On June 12, 2013, the Indian government suspended the manufacture, sale, and distribution of the drug under Section 26A of the 1940 Drugs and Cosmetic Act.{{cite web | url = http://www.thehindu.com/sci-tech/health/medicine-and-research/govt-bans-painkiller/article4808001.ece | work = The Hindu | title = Govt. bans painkiller | date = 13 June 2013 }}

In Sweden, physicians had long been discouraged by the medical products agency to prescribe dextropropoxyphene due to the risk of respiratory depression and even death when taken with alcohol.{{cite web |url = http://www.lakemedelsverket.se/Tpl/NewsPage____495.aspx |title = Fasta kombinationer av smärtstillande läkemedel innehållande dextropropoxifen försvinner från marknaden under hösten 2005 |trans-title = Fixed combinations of analgesic drugs containing dextropropoxyphene disappear from the market in the autumn of 2005 |language = sv |publisher = Läkemedelsverket |date = 5 May 2005 |access-date = 22 April 2007 |archive-url = https://web.archive.org/web/20070927205836/http://www.lakemedelsverket.se/Tpl/NewsPage____495.aspx |archive-date = 27 September 2007 |url-status = dead }} Physicians had earlier been recommended to prescribe products with only dextropropoxyphene and not to patients with a history of substance use disorder, depression, or suicidal tendencies. Products with mixed active ingredients were taken off the market and only products with dextropropoxyphene were allowed to be sold. Dextropoxyphene was de facto narcotica labelled.

As of March 2011, all products containing the substance are withdrawn because of safety issues after a European Commission decision.{{cite web | title = Dextropropoxyphene | url = https://www.ema.europa.eu/en/medicines/human/referrals/dextropropoxyphene | work = European Medicines Agency | date = 17 September 2018 | quote = On 25 June 2009, the European Medicines Agency ... recommended that all marketing authorisations for dextropropoxyphene-containing medicines should be withdrawn throughout the European Union (EU). }}{{cite web |url=http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2010/Dextropropoxifen-dras-bort-fran-marknaden/ |title=Dextropropoxyphene is removed from the market |language=sv |date=5 May 2005 |work=Läkemedelsverket |access-date=1 February 2011 |archive-date=22 July 2011 |archive-url=https://web.archive.org/web/20110722071405/http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2010/Dextropropoxifen-dras-bort-fran-marknaden/ |url-status=dead }}

At the time, people who drank excessive amounts of alcohol and other substances and take combination dextropoxyphene / acetaminophen (paracetamol) were discussed as needing to take many combination tablets to reach euphoria, because the amount of dextropropoxyphene per tablet is relatively low (30–40 mg). The ingested paracetamol—the other component—may then reach liver toxic levels. In the case of alcoholics, who often already have damaged livers, even a relatively small overdose with paracetamol may produce hepatotoxicity, liver failure, and necrosis. This toxicity with the combination of overdosed dextroproxyphene (with its CNS/respiratory depression/vomit with risk for aspiration pneumonia, as well as cardiotoxicity) and paracetamol-induced liver damage can result in death.

In the United Kingdom, preparations containing only dextropropoxyphene were discontinued in 2004.{{cite web | url = http://news.bbc.co.uk/1/hi/health/4221829.stm | title = Painkiller Scrapped Over Suicides | work = BBC News | date = 31 January 2005 }} In 2007, the Medicines and Healthcare products Regulatory Agency removed the licence for co-proxamol, also called distalgesic.{{Cite web|url = http://www.netdoctor.co.uk/aches-and-pains/medicines/distalgesic.html|title = Distalgesic (discontinued in the UK - December 2007)|date = 9 January 2008|access-date = 8 September 2013|website = netdoctor|archive-date = 29 June 2013|archive-url = https://web.archive.org/web/20130629182009/http://www.netdoctor.co.uk/aches-and-pains/medicines/distalgesic.html|url-status = dead}} From then on in the UK, co-proxamol is only available on a named patient basis, for long-term chronic pain and only to those who have already been prescribed this medicine. Its withdrawal from the UK market is a result of concerns relating to its toxicity in overdose (even small overdoses can be fatal), and dangerous reaction with alcohol. Recreational use in the UK is uncommon. Many patients have been prescribed alternative combinations of drugs as a replacement.

The motivation for the withdrawal of co-proxamol was the reduction in suicides and a key part of the agency's justification of its decision was based upon studies showing co-proxamol was no more effective than paracetamol alone in pain management.{{cite report | vauthors = Duff G | title = Withdrawal of co-proxamol products and interim updated prescribing information. | work = Medicines and Healthcare Products Regulatory Agency | date = 31 January 2005 | url = https://assets.publishing.service.gov.uk/media/547307ede5274a1303000023/con019461.pdf }}{{cite web | url = https://www.gov.uk/drug-safety-update/co-proxamol-withdrawal-reminder-to-prescribers | title = Co-proxamol withdrawal: reminder to prescribers | work = Medicines and Healthcare products Regulatory Agency (MHRA) | date = 11 December 2014 }}

The co-proxamol preparations available in the UK contained a subtherapeutic dose of paracetamol, 325 mg per tablet.[http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019462 "Co-proxamol: outcome of the review of risks and benefits"]{{Dead link|date=July 2019 |bot=InternetArchiveBot |fix-attempted=yes }}. Questions and Answers leaflet, Retrieved August 28, 2009 Patients were warned not to take more than eight tablets in one day, a total dose of 2600 mg paracetamol per day. Despite this reduced level, patients were still at a high risk of overdose; coproxamol was second only to tricyclic antidepressants as the most common prescription drugs used in overdose. Following the reduction in prescribing in 2005–2007, prior to its complete withdrawal, the number of deaths associated with the drug dropped significantly. Additionally, patients have not substituted other drugs as a method of overdose.{{cite journal | vauthors = Hawton K, Bergen H, Simkin S, Brock A, Griffiths C, Romeri E, Smith KL, Kapur N, Gunnell D | title = Effect of withdrawal of co-proxamol on prescribing and deaths from drug poisoning in England and Wales: time series analysis | journal = BMJ | volume = 338 | pages = b2270 | date = June 2009 | pmid = 19541707 | pmc = 3269903 | doi = 10.1136/bmj.b2270 }}

The decision to withdraw co-proxamol has met with some controversy; it has been brought up in the House of Commons on two occasions, 13 July 2005{{cite web | url = https://www.theyworkforyou.com/debates/?id=2005-07-13a.936.0 | title = Co-Proxamol | date = 13 July 2005 | work = House of Commons debates (TheyWorkForYou.com) }} and on 17 January 2007.{{cite web | url = https://www.theyworkforyou.com/whall/?id=2007-01-17b.340.0| title = Co-proxamol | date = 17 January 2007 | work = Westminster Hall debates (TheyWorkForYou.com) }} Patients have found alternatives to co-proxamol either too strong, too weak, or with intolerable side effects.{{Citation needed|date=August 2009}} During the House of Commons debates, it is quoted that originally some 1,700,000 patients in the UK were prescribed co-proxamol. Following the phased withdrawal, this has eventually been reduced to 70,000. However, this apparently is the residual pool of patients who cannot find alternate analgesia to co-proxamol.{{Citation needed|date=August 2009}}

The safety net of prescribing co-proxamol after license withdrawal from 31 December 2007, on a "named patient" basis where doctors agree a clinical need exists, has been rejected by most UK doctors{{Citation needed|date=August 2009}} because the wording that "responsibility will fall on the prescriber" is unacceptable to most doctors. Some patients intend to take the case to the European Court of Human Rights.{{Cite web | vauthors = McLean R | date = 6 January 2008 |url=http://www.medicalnewstoday.com/youropinions.php?opinionid=25173 |title=Failure Of MHRA Coproxamol Named Patient System | work = Visitor Opinion | publisher = Medical News Today |access-date=2008-01-08 |archive-date=2008-11-21 |archive-url=https://web.archive.org/web/20081121205724/http://www.medicalnewstoday.com/youropinions.php?opinionid=25173 |url-status=dead }} However, the European Medicines Agency has recently backed the agency's decision, and recommended in June 2009 that propoxyphene preparations be withdrawn across the European Union.{{Cite web |url=http://www.mhra.gov.uk/NewsCentre/CON049300 |title=News Centre : MHRA |access-date=2009-08-28 |archive-url=https://web.archive.org/web/20090917062943/http://www.mhra.gov.uk/NewsCentre/CON049300 |archive-date=2009-09-17 |url-status=dead }}

On 28 March 2017, NHS Clinical Commissioners announced that co-proxamol will be no longer available under NHS England as part of £400m of spending cuts for prescriptions that are believed to have little or no clinical value.{{Cite news|url=https://www.bbc.co.uk/news/health-39413915|title=NHS targets suncream prescriptions for cuts| vauthors = Triggle N |date=2017-03-28|work=BBC News|access-date=2017-03-28|language=en-GB}}

In January 2009, an FDA advisory committee voted 14 to 12 against the continued marketing of propoxyphene products, based on its weak pain-killing abilities, addictiveness, association with drug deaths and possible heart problems, including arrhythmia. A subsequent re-evaluation resulted in a July 2009 recommendation to strengthen the boxed warning for propoxyphene to reflect the risk of overdose.{{cite news | title = FDA Takes Actions on Darvon, Other Pain Medications Containing Propoxyphene | publisher = U.S. Food and Drug Administration (FDA) | date = 7 July 2009 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170769.htm}} Dextropropoxyphene subsequently carried a black box warning in the U.S., stating:

Propoxyphene should be used with extreme caution, if at all, in patients who have a history of substance/drug/alcohol abuse, depression with suicidal tendency, or who already take medications that cause drowsiness (e.g., antidepressants, muscle relaxants, pain relievers, sedatives, tranquilizers). Fatalities have occurred in such patients when propoxyphene was misused.{{cite web | url = http://www.webmd.com/drugs/drug-4998-Darvocet-N+100+Oral.aspx?drugid=4998&drugname=Darvocet-N+100+Oral#precautions | title = Drug Information for Darvocet-N 100 Oral | work = Web MD }}

Because of potential for side effects, this drug is on the list for high-risk medications in the elderly.{{cite web | url = http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf | title = NCQA's HEDIS Measure: Use of High Risk Medications in the Elderly | work = National Committee for Quality Assurance (NCQA) | location = Washington, D.C. | archive-url = https://web.archive.org/web/20100201113909/http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf | archive-date=February 1, 2010 }}

On November 19, 2010, the FDA requested manufacturers withdraw propoxyphene from the US market, citing heart arrhythmia in patients who took the drug at typical doses.{{cite news|title=Darvon, Darvocet painkillers pulled from the U.S. market | vauthors = Zajac A |newspaper=L.A. Times |date=November 19, 2010 |url=http://www.latimes.com/news/nationworld/nation/sc-dc-1120-fda-darvon-web-20101119,0,6525838.story |access-date=November 19, 2010 |url-status=dead |archive-url=https://web.archive.org/web/20101122093848/http://www.latimes.com/news/nationworld/nation/sc-dc-1120-fda-darvon-web-20101119,0,6525838.story |archive-date=November 22, 2010 }} Tramadol, which lacks the cardiotoxicity, has been recommended instead of propoxyphene, as it is also indicated for mild to moderate pain, and is less likely to be misused or cause addiction than other opioids.{{cite journal | vauthors = Lin FS, Lin WY, Lai CH, Chen CY, Lin CP, Lin TF, Sun WZ | title = Analgesic efficacy of tramadol/acetaminophen and propoxyphene/acetaminophen for relief of postoperative wound pain | journal = Acta Anaesthesiologica Taiwanica | volume = 50 | issue = 2 | pages = 49–53 | date = June 2012 | pmid = 22769857 | doi = 10.1016/j.aat.2012.05.009 | doi-access = free }}

In the Stephen King short story collection Night Shift, the final story of the book, "The Woman in the Room", tells a tale in which the main character contemplates and then finally performs a mercy killing using a drug called "Darvon Complex."

High toxicity and relatively easy availability made propoxyphene a drug of choice for right-to-die societies. It is listed in Dr. Philip Nitschke's The Peaceful Pill Handbook and Dr. Pieter Admiraal's Guide to a Humane Self-Chosen Death.{{cite book|title=The Peaceful Pill Handbook|publisher=Exit International|location=U.S.|year=2006|isbn=978-0-7817-3481-3| vauthors = Nitschke P, Stewart F }}{{cite book | vauthors = Admiraal P, Chabot B, Ogden RD, Rietveld A, Glerum J |title=Guide to a Humane Self-Chosen Death |edition=Second expanded |date=2006 |location=Delft | publisher = WOZZ Foundation |isbn=978-90-78581-01-7| oclc = 1100586437 }} "With the withdrawal of the barbiturate sleeping tablets from the medical prescribing list, propoxyphene has become the most common doctor-prescribed medication used by seriously ill people to end their lives."

• Ketobemidone
• Levopropoxyphene
• Meperidine

{{Reflist|30em}}

{{Analgesics}}

{{Navboxes

| title = Pharmacodynamics

| titlestyle = background:#ccccff

| list1 =

{{Ion channel modulators}}

{{Ionotropic glutamate receptor modulators}}

{{Monoamine reuptake inhibitors}}

{{Nicotinic acetylcholine receptor modulators}}

{{Opioid receptor modulators}}

}}

Category:Synthetic opioids

Category:Dimethylamino compounds

Category:Antitussives

Category:Combination analgesics

Category:Drugs developed by Eli Lilly and Company

Category:Hepatotoxins

Category:HERG blocker

Category:Mu-opioid receptor agonists

Category:NMDA receptor antagonists

Category:Propionate esters

Category:Withdrawn drugs

Category:Potassium channel blockers