Dextropropoxyphene 1078828 224727637 2008-07-10T04:00:35Z SlashComma 6797881 [[WP:UNDO|Undid]] revision 224479289 by [[Special:Contributions/72.48.164.230|72.48.164.230]] ([[User talk:72.48.164.230|talk]]) - vandalism {{Cleanup|date=March 2008}} {{Drugbox| |IUPAC_name = [(2R,3R)-4-dimethylamino- 3-methyl-1,2-diphenyl-butan-2-yl] propanoate | image=DPropoxyphene.png | image_size=200 | CAS_number=469-62-5 | ATC_prefix=N02 | ATC_suffix=AC04 | ATC_supplemental= | PubChem=10100 | smiles = CCC(=O)O[C@@](Cc1ccccc1)([C@H](C)CN(C)C)c1ccccc1 | DrugBank=DB00647 | chemical_formula = C<sub>22</sub>H<sub>29</sub>NO<sub>2</sub> | melting_point = 75 | molecular_weight = 339.471 | elimination_half-life= 3.6&ndash;6.5 hours<ref name="pmid1150913">{{cite journal |author=Slywka GW, Melikian AP, Whyatt PL, Meyer MC |title=Propoxyphene bioavailability: an evaluation of ten products |journal=[[J Clin Pharmacol]] |volume=15 |issue=8-9 |pages=598–604 |year=1975 |pmid=1150913 |doi= |url=http://jcp.sagepub.com/cgi/pmidlookup?view=long&pmid=1150913 |issn= |accessdate=2008-06-16}}</ref> | pregnancy_category = C, D for prolonged use (US) | legal_status = [[Controlled Substances Act#Schedule IV drugs|Schedule IV]] (in dosage form) ([[United States of America|US]]) | legal_AU = S4 | routes_of_administration = oral }} '''Dextropropoxyphene''' is an [[analgesic]] in the [[opioid]] category. It is used to treat mild to moderate pain and as an [[anti-tussive]]. It can be used to ease surgical pain both prophylactically and palliatively. It is possible to classify it as a mild opioid pain-killer, however it is considered no more effective than [[aspirin]] in treating pain.<ref>Nursing Drug Handbook, Springhouse, page 324</ref> Dextropropoxyphene is sometimes combined with [[paracetamol]] (acetaminophen) or [[aspirin]]. Trade-names include [[Darvocet|Darvocet-N]] for dextropropoxyphene and [[paracetamol]] and [[Darvon|Darvon-N with ASA]] for dextropropoxyphene and [[aspirin]].<ref>Nursing Drug Handbook, Springhouse, page 306</ref><ref>The paracetamol combination(s) are known as co-proxamol or in the [[United Kingdom|UK]] and Capadex or Di-Gesic in [[Australia]].</ref> It is also sometimes sold in combination with caffeine in order to boost pain control.<ref>Nursing Drug Handbook, Springhouse, page 324</ref><ref>There is conflicting evidence as to whether it improves pain control. Nursing Drug Handbook, Springhouse, page 419</ref> There is no [[peer-review]]ed evidence that this combination is any more effective than [[paracetamol]] alone. There is significant anecdotal evidence from patients that [[Darvocet]] is more effective than paracetamol, but a third of patients suffering chronic pain report relief from that pain when treated with placebo. It is manufactured and marketed by [[Eli Lilly and Company]]. It is an [[optical isomer]] of [[levopropoxyphene]]. The [[racemate|racemic mixture]] is called propoxyphene. Some preparations that contain dextropropoxyphene include ''Distalgesic'' and ''Doloxene''. ==Indications== {{Unreferencedsection|date=March 2008}} === Analgesia === Dextropropoxyphene, like [[codeine]], is a "weak" opioid. Codeine is more commonly used; however, some individuals (approximately 10-20% of the [[Caucasian race|Caucasian]] population) are unable to metabolize it, due to poor functioning of the enzyme [[CYP2D6]]. It is in these people that dextropropoxyphene is particularly useful, as its metabolism does not require CYP2D6. ===(RLS) Restless Legs Syndrome=== Propoxyphene has been found to be helpful in relieving the symptoms of [[Restless legs syndrome]] (RLS). === 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. Dextropropoxyphene is subject to some controversy: while many [[physician]]s 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. [[Image:propoxyphene.jpg|thumb|left]] The [[therapeutic index]] of dextroproxyphene is relatively small. In the [[UK]], dextropropoxyphene and co-proxamol are now discouraged from general use; and, since 2004, preparations containing only dextropropoxyphene have been discontinued. This has been a somewhat controversial decision, since it has caused abusers to switch to the combined product and risk paracetamol toxicity. [[Australia]] declined to follow suit and opted to allow pure dextropropoxyphene to remain available by prescription. From 31st December 2007, 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 more potent drugs. 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 (32.5mg dextropropoxyphene per 325mg [[paracetamol]] branded as either "Di-gesic", "Capadex", and "Paradex," it is also available in pure form (100 mg capsules) known as "Doloxene". [[Image:propoxyphene2.jpg|thumb|right]] ==Adverse effects== 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 to achieve [[Euphoria (emotion)|euphoria]]. They suffer acute [[hepatotoxicity|liver toxicity]], which causes severe [[stomach pains]], [[nausea]], and [[vomiting]] (all of which are increased by light or stimulation of the sense of sight). Dextropropoxyphene also has several other non-opioid side-effects. Both propoxyphene and its metabolite norpropoxyphene, have local [[anesthetic]] effects at concentrations about 10 times those necessary for opioid effects. In this respect, [[norpropoxyphene]] is more potent than propoxyphene, and they are both more potent than [[lidocaine]].<ref name=Nickander1>Nickander ''et al.'', 1984</ref> Both propoxyphene and norpropoxyphene also have direct cardiac effects which include decreased [[heart rate]], decreased [[contractility]], and decreased [[electrical conductivity]] (ie, increased PR, AH, HV, and QRS intervals). Norpropoxyphene is several times more potent than propoxyphene in this activity. These effects appear to be due to their local anesthetic activity and are not reversed by [[naloxone]].<ref name=Nickander1/><ref name=Bredgaard1>Bredgaard, Sorensen ''et al.'', 1984</ref><ref name=Strom1>Strom ''et al.'', 1985b</ref> Both propoxyphene and norpropoxyphene are potent blockers of [[cardiac membrane]] [[sodium channels]] and are more potent than [[lidocaine]], [[quinidine]], and [[procainamide]] in this respect.<ref name=Holland1>Holland & Steinberg, 1979</ref> Propoxyphene and norpropoxyphene appear to have the characteristics of a [[Antiarrhythmic agent#Class Ic agents|Vaughan Williams Class Ic antiarrhythmic]]. Darvon, a dextropropxyphene made by [[Eli Lilly and Company|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, but Lilly has waged a sweeping, and largely successful, campaign among doctors, pharmacists and Darvon users to defend the drug as safe when it is used in proper doses and not mixed with alcohol. 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. <ref>http://www.lakemedelsverket.se/Tpl/NewsPage____495.aspx</ref> 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. In the United Kingdom, the Medicines & Healthcare Regulatory Authority (MHRA) removed the licence for co-proxamol on 31st December 2007. Whilst the MHRA are to be commended for their motivation in trying to reduce the number of suicides through misuse of co-proxamol, the decision has proven controversial twice reaching the rarefied heights of a UK Parliament House of Commons Adjournment Debate. On 13th July 2005<ref>http://www.theyworkforyou.com/debates/?id=2005-07-13a.936.0</ref> and on 17th January 2007.<ref>http://www.theyworkforyou.com/whall/?id=2007-01-17b.340.0</ref> The problem that has arisen is many patients have found alternatives to co-proxamol either too strong, too weak, or with intolerable side effects. 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. To make matters worse, the MHRA safety net of prescribing co-proxamol after licence withdrawal from 31st December 2007 on a "Named Patient" basis where doctors agree there is a clinical need, has been rejected by most UK doctors because the MHRA wording that "responsibility will fall on the prescriber" is unacceptable to most doctors. As a result of many UK citizens now in untreated pain, there are now several patients lining up to launch a "Class Action" lawsuit against the MHRA.<ref>http://www.medicalnewstoday.com/youropinions.php?opinionid=25173</ref> ==Chemistry== ===Hydrochloride and napsylate salts=== 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 <ref>{{cite book|isbn=0781734819|title=Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry|authors=Wilson, Charles Owens and Gisvold, John H|publisher=Lippincott Williams & Wilkins}}</ref>. 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. ==Toxicologic mechanism== A) 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. B) Local anesthetic activity appears to be responsible for the [[arrhythmias]] and [[cardiovascular depression]] seen in propoxyphene poisoning.<ref name=Strom1/> 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.<ref name=Stork1>Stork ''et al.'', 1995</ref> C) [[Seizure]]s may result from either opioid or local anesthetic effects.<ref name=Nickander1/> D) [[Pulmonary edema]] may result from direct [[pulmonary toxicity]], [[neurogenic]]/[[Hypoxia (medical)|anoxic]] effects, or cardiovascular depression.<ref name=Strom1/> == Caution == Caution should be used when administering dextropropoxyphene, particularly with children and the elderly and with patients who may be pregnant or breast feeding; 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. == Contraindication == Allergy to paracetamol or dextropropoxyphene, alcoholism. ==Recreational use== Those who take dextropropoxyphene for recreational purposes take larger than therapeutic doses and, if it is not [[cold water extraction|extracted]], the [[paracetamol]] (acetaminophen) that is present in combination products can be [[hepatotoxicity|toxic to the liver]]. Some adverse effects of recreational dextropropoxyphene use are: a persistent [[dry mouth]], [[decreased appetite]], [[urinary retention]] and [[constipation]], and or Diarrhea that may lead to [[diverticulitis]]. ==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"<ref name=PeacefulPillHandbook>{{cite book|title=The Peaceful Pill Handbook|authors=Nitschke, Philip & Fiona Stewart|publisher=Exit International|location=U.S.|date=2006|isbn=0978878817}}</ref> and Dr Pieter Admiraal's "Guide to a Humane Self-Chosen Death"<ref>{{cite book|title=Guide to a Humane Self-Chosen Death|authors=Dr. Pieter Admiraal et al.|publisher=WOZZ Foundation, Delft|location=The Netherlands|isbn=9078581018}}</ref>. "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." <ref name=PeacefulPillHandbook/>. Slang name for the combination of propoxyphene and other drugs used for suicide is [[wiktionary:Darvon cocktail|"Darvon cocktail"]]. ==References== {{reflist}} {{Analgesics}} {{Opioids}} [[Category:Antitussives]] [[Category:Eli Lilly and Company]] [[Category:Opioids]] [[es:Dextropropoxifeno]] [[fr:Dextropropoxyphène]] [[ro:Dextropropoxifen]] [[fi:Dekstropropoksifeeni]] [[sv:Dextropropoxifen]] [[th:เดกซ์โตรโพรพอไซฟีน]]