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Dextropropoxyphene

Dextropropoxyphene
Systematic (IUPAC) name
(1S,2R)-1-benzyl-3-(dimethylamino)-2-methyl-1-phenylpropyl propionate
Identifiers
CAS number 469-62-5
ATC code N02AC04
PubChem 10100
DrugBank DB00647
ChemSpider 9696
Chemical data
Formula C22H29NO2 
Mol. mass 339.471 g/mol
SMILES eMolecules & PubChem
Physical data
Melt. point 75 °C (167 °F)
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life 3.6–6.5 hours[1]
Excretion  ?
Therapeutic considerations
Pregnancy cat. C, D for prolonged use (US)
Legal status Prescription Only (S4) (AU) Schedule II, Schedule IV (in dosage form) (US)
Routes oral, IV, rectal.
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Dextropropoxyphene, manufactured by Eli Lilly and Company, is an analgesic in the opioid category. It is used to treat mild pain and is additionally an anti-tussive and local anesthetic.

Dextropropoxyphene is sometimes combined with acetaminophen or acetylsalicylic acid. Trade-names include Darvocet-N and Di-Gesic[2] Darvon with APAP for dextropropoxyphene and paracetamol and Darvon with ASA for dextropropoxyphene and aspirin.[3] The paracetamol combination(s) are known as Capadex or Di-Gesic in Australia, Lentogesic in South Africa, and Di-Antalvic in France. The paracetamol preparation is known as co-proxamol in the UK, but has been withdrawn since 2007 and is no longer available to new patients.[4]

Indications

Analgesia

Dextropropoxyphene, like codeine, is a weak opioid, known to cause dependency among recreational users. Codeine is more commonly used; however, as codeine is, in essence, a prodrug that requires in vivo metabolism to the more active opioid morphine for maximum efficacy, it is ineffective for some individuals with the "poor metabolizer" genotype of the liver Cytochrome P450 enzyme CYP2D6. It is in people with this low-function isoform of the CYP2D6 gene that dextropropoxyphene is particularly useful, as its metabolism does not require CYP2D6. It is also used for patients with digestive complaints as it is less liable to worsen their symptoms.

Restless legs syndrome (RLS)

Propoxyphene has been found to be helpful in relieving the symptoms of restless legs syndrome (RLS). [5][6][7]

Opioid withdrawal

In pure form, dextropropoxyphene is commonly used to ease the withdrawal symptoms in people addicted to opioids. Being very weak in comparison to the opioids that are commonly abused, dextropropoxyphene can only act as a "partial" substitute. It does not have much effect on mental cravings; however it can be effective in alleviating physical withdrawal effects, such as muscle cramps.

Contraindications

Allergy to paracetamol or dextropropoxyphene; alcoholism; combination with amphetamine. Not intended for use in patients who are prone to suicide or addiction.

Pharmacology

Dextropropoxyphene acts as a mu-opioid receptor agonist. It also acts as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist[8], as well as weak serotonin reuptake inhibitor.

Toxicity

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

Many users experience toxic effects from the paracetamol (acetaminophen) in pursuit of the endlessly-increasing dose required for pain relief. They suffer acute liver toxicity, which causes severe stomach pains, nausea, and vomiting (all of which are increased by light or stimulation of the sense of sight).

An overdose of dextropropoxyphene may lead to various systemic effects. Excessive opioid receptor stimulation is responsible for the CNS depression, respiratory depression, miosis, and gastrointestinal effects seen in propoxyphene poisoning. It may also account for mood/thought altering effects.

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.[9] Local anesthetic activity appears to be responsible for the arrhythmias and cardiovascular depression seen in propoxyphene poisoning.[10]

Both propoxyphene and norpropoxyphene are potent blockers of cardiac membrane sodium channels and are more potent than lidocaine, quinidine, and procainamide in this respect.[11] 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.[9][10][12] 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.[13]

Seizures may result from either opioid or local anesthetic effects.[9] Pulmonary edema may result from direct pulmonary toxicity, neurogenic/anoxic effects, or cardiovascular depression.[10]

Available forms

Propoxyphene was initially introduced as propoxyphene hydrochloride. Shortly before the patent on propoxyphene expired, propoxyphene napsylate form was introduced to the market. Napsylate salt is claimed to be less prone to abuse, because it is almost insoluble in water and therefore cannot be used for injection. Napsylate also gives lower peak blood level.[14] Because of different molecular mass, a dose of 100 mg of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg propoxyphene hydrochloride.

In the United States, dextropropoxyphene HCl is available as a prescription formulation with paracetamol (acetaminophen) in ratio anywhere 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." On the other hand, "Darvon" is a pure propoxyphene preparation available in the U.S. 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 either "Di-gesic", "Capadex", and "Paradex," it is also available in pure form (100 mg capsules) known as "Doloxene".

Usage controversy and regulation

Trade Name: Doloxene - 100 mg - dextropropoxyphene napsylate

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.[citation needed] In addition, the therapeutic index of dextroproxyphene is relatively small.

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

Darvon, a dextropropoxyphene 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.[citation needed] Darvon was never withdrawn from the market, but Lilly has waged a sweeping, and largely successful, campaign[citation needed] among doctors, pharmacists and Darvon users to defend the drug as safe when it is used in proper doses and not mixed with alcohol.

United Kingdom

In the United Kingdom, preparations containing only dextropropoxyphene were discontinued in 2004.[15] In 2007, the Medicines and Healthcare products Regulatory Agency (MHRA) removed the licence for co-proxamol. From then onwards, 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 overdose 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.[16]

The MHRA's motivation for the withdrawal of co-proxamol was the reduction in suicides and a key part of its justification of its decision was based upon studies showing that co-proxamol was no more effective than paracetamol alone in pain management.[17] Prescribing authorities such as the Royal College of General Practitioners unanimously recommended withdrawal, while patients who responded to the MHRA's request for information tended to want to continue treatment. [18] Many doctors as well as patients believe that clinical experience shows co-proxamol is more effective than paracetamol alone.[citation needed]

The co-proxamol preparations available in the UK contained a sub-therapeutic dose of paracetamol, 325 mg per tablet[19]. Patients were warned not to take more than 8 tablets in one day, a total dose of 2600 mg paracetamol per day. This is in comparison to the 4000 mg daily limit on paracetamol alone, a significantly higher dose. 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. [17] 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. [20]

The decision to withdraw coproxamol has met with some controversy; it has been brought up in the House of Commons on two occasions, 13 July 2005[21] and on 17 January 2007.[22] Patients have found alternatives to co-proxamol either too strong, too weak, or with intolerable side effects.[citation needed] 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 MHRA phased withdrawal this has eventually been reduced to 70,000. However, it appears this is the residual pool of patients who cannot find alternate analgesia to co-proxamol.[citation needed]

The MHRA safety net of prescribing co-proxamol after licence withdrawal from 31 December 2007 on a "Named Patient" basis where doctors agree there is a clinical need, has been rejected by most UK doctors[citation needed] because the MHRA 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.[23] However, the European Medicines Agency has recently backed the MHRA's decision, and recommended in June 2009 that propoxyphene preparations be withdrawn across the European Union.[24]

European Union

In November 2007 the European Commission requested the European Medicines Agency (EMEA) to review the safety and effectiveness of dextropropoxyphene based medicines and on 25 June 2009 the EMEA recommended a gradual withdrawal throughout the European Union. The EMEA'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 that the difference between the dose needed for treatment and a harmful dose (the "therapeutic index") was too small.[25]

Australia

In Australia, both pure dextropropoxyphene capsules (as napsylate, 100mg), marketed as "Doloxene", and combination tablets and capsules (with paracetamol) all containing 32.5mg dextropropoxyphene HCl with 325mg paracetamol, continue to remain available by prescription. [26]

Sweden

In Sweden physicians have been discouraged by the medical products agency to prescribe dextropropoxyphene due to the risk of respiratory depression when taken with alcohol.[27] Products with other active ingredients have been taken off the market and only products with only dextropropoxyphene are supposed to be sold. Physicians are recommended only to prescribe products with only dextropropoxyphene and not to patients with a history of drug abuse, depression or suicidal tendencies. The combination of dextropropoxyphene HCl and paracetamol sold under the name "Distalgesic" is no longer available in Sweden. Other products sold are "Doloxene" and "Dexofen" both containing dextropropoxyphene napsylate.

  • It was discussed at the time that people who abuse alcohol and other substances and take combination dextropoxyphene/acetaminophen (paracetamol) may need to take many combination tablets to reach euphoria. This is because the amount of dextropropoxyphene per tablet is relatively low (30-40mg). 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 . The toxicity of the combination of overdosed dextropoxyphene with its CNS/respiratory depression and paracetamols liver damage can be a recipe for disaste or death. This is also true for any person with a already damaged or weakened liver by disease or otherwise.

United States

A U.S. Food and Drug Administration (FDA) panel recently voted to recommend that dextropropoxyphene be removed from the market, 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.[28] Dextropropoxyphene currently carries 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.[29]

Because of potential for side effects, this drug is on the list for High Risk Medications in the elderly. (See NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly, http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf).

Use by right to die societies

High toxicity and relatively easy availability made propoxyphene drug of choice for right to die societies. Propoxyphene is listed in Dr. Philip Nitschke's "Peaceful Pill Handbook"[30] and Dr Pieter Admiraal's "Guide to a Human Self-Chosen Death"[31]. "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.".[30] Slang name for the combination of propoxyphene and other drugs used for suicide is "Darvon cocktail".[32]

References

  1. ^ Slywka GW, Melikian AP, Whyatt PL, Meyer MC (1975). "Propoxyphene bioavailability: an evaluation of ten products". J Clin Pharmacol 15 (8-9): 598–604. PMID 1150913. http://jcp.sagepub.com/cgi/pmidlookup?view=long&pmid=1150913. Retrieved 2008-06-16. 
  2. ^ "Consumer Medicine Information: Digesic". Aspen Pharmacare Australia Pty Ltd. http://www.aspenpharma.com.au/PDF/CMI/CMI_Digesic.pdf. 
  3. ^ Nursing Drug Handbook, Springhouse, page 306
  4. ^ BNF Edition 57, BNF.org
  5. ^ "Restless legs syndrome: Definition from". Answers.com. http://www.answers.com/topic/restless-legs-syndrome. Retrieved 2009-08-19. 
  6. ^ "Restless Leg Syndrome - Sleep Medicine Centers of WNY". Sleepmedicinecenters.com. http://www.sleepmedicinecenters.com/Home/SleepDisorders/RestlessLegsSyndrome. Retrieved 2009-08-19. 
  7. ^ "Causes, diagnosis and treatment for the patient living with Restless Legs Syndrome (RLS)". Restless Leg Syndrome Foundation. 1 April 2006. http://www.rls.org/Document.Doc?&id=3. Retrieved 2009-08-19. 
  8. ^ "Blockade of Rat α3β4 Nicotinic Receptor Function by Methadone, Its Metabolites, and Structural Analogs — JPET". http://jpet.aspetjournals.org/content/299/1/366.abstract. 
  9. ^ a b c Nickander et al., 1984
  10. ^ a b c Strom et al., 1985b
  11. ^ Holland & Steinberg, 1979
  12. ^ Bredgaard, Sorensen et al., 1984
  13. ^ Stork et al., 1995
  14. ^ Wilson, Charles Owens and Gisvold, John H. Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry. Lippincott Williams & Wilkins. ISBN 0781734819. 
  15. ^ Painkiller Scrapped Over Suicides
  16. ^ BNF.org, BNF edition 57, accessed 28th August 2009
  17. ^ a b http://www.mhra.gov.uk/Safetyinformation/
  18. Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/con019461 MHRA Letter to Healthcare Professionals, accessed August 28th 2009
  19. ^ http://www.mhra.gov.uk/Safetyinformation/
  20. Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/con019463
  21. ^ http://www.mhra.gov.uk/Safetyinformation/
  22. Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019462 MHRA Questions and Answers leaflet, accessed August 28th, 2009
  23. ^ http://www.bmj.com/cgi/content/abstract/338/jun18_2/b2270 British Medical Journal, Effect of withdrawal of co-proxamol on prescribing and deaths from drug poisoning in England and Wales: time series analysis, article accessed August 28th 2009
  24. ^ Co-Proxamol: 13 Jul 2005: House of Commons debates (TheyWorkForYou.com)
  25. ^ Co-proxamol: 17 Jan 2007: Westminster Hall debates (TheyWorkForYou.com)
  26. ^ Failure Of MHRA Coproxamol Named Patient System - Visitor Opinion
  27. ^ http://www.mhra.gov.uk/NewsCentre/CON049300
  28. ^ "Questions and answers on the withdrawal of the marketing authorisations for medicines containing dextropropoxyphene". http://www.emea.europa.eu/pdfs/human/referral/dextropropoxyphene/40106109en.pdf. Retrieved 2009-09-08. 
  29. ^ MIMS No. 2 2008 Section 4a
  30. ^ "Fixed combinations of analgesic drugs containing dextropropoxyphene to be removed from the market in the autumn of 2005" (in swedish). 5 May 2005. http://www.lakemedelsverket.se/Tpl/NewsPage____495.aspx. 
  31. ^ "FDA Takes Actions on Darvon, Other Pain Medications Containing Propoxyphene". FDA News release. 7 July 2009. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm170769.htm. 
  32. ^ Drug Information for Darvocet-N 100 Oral - Web MD
  33. ^ a b Nitschke, Philip & Fiona Stewart (2006). The Peaceful Pill Handbook. U.S.: Exit International. ISBN 0978878817. 
  34. ^ Dr. Pieter Admiraal et al.. Guide to a Humane Self-Chosen Death. The Netherlands: WOZZ Foundation, Delft. ISBN 9078581018. 
  35. ^ ASH Wiki: Darvon Cocktail


 

The content of this section is licensed under the GNU Free Documentation License (local copy). It uses material from the Wikipedia article "Dextropropoxyphene" modified November 23, 2009 with previous authors listed in its history.