Dextropropoxyphene is an

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

in the

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

category, patented in 1955 and manufactured by

Eli Lilly and Company Eli Lilly and Company, Trade name, doing business as Lilly, is an American multinational Medication, pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 count ...

. It is an

optical isomer In chemistry, a molecule or ion is called chiral () if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality (). The terms are de ...

of levopropoxyphene. It is intended to treat mild pain and also has

antitussive Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including ana ...

(cough suppressant) and

local anaesthetic A local anesthetic (LA) is a medication that causes absence of all sense, sensation (including pain) in a specific body part without loss of consciousness, providing local anesthesia, as opposed to a general anesthetic, which eliminates all sen ...

effects. The drug has been taken off the market in Europe and the US due to concerns of fatal overdoses and heart arrhythmias. It is still available in Australia, albeit with restrictions after an application by its manufacturer to review its proposed banning. Its onset of analgesia (pain relief) is said to be 20–30 minutes and peak effects are seen about 1.5–2.0 hours after oral administration. Dextropropoxyphene is sometimes combined with

acetaminophen Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...

. Trade names include Darvocet-N, Di-Gesic, and Darvon with APAP (for dextropropoxyphene and paracetamol). The

British approved name A British Approved Name (BAN) is the official, non-proprietary, or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia (BP). The BAN is also the official name used in some countries around the world, because ...

(i.e. the generic name of the active ingredient) of the paracetamol/dextropropoxyphene preparation is co-proxamol (sold under a variety of brand names); however, it has been withdrawn since 2007, and is no longer available to new patients, with exceptions. The paracetamol combination(s) are known as Capadex or Di-Gesic in

Australia Australia, officially the Commonwealth of Australia, is a country comprising mainland Australia, the mainland of the Australia (continent), Australian continent, the island of Tasmania and list of islands of Australia, numerous smaller isl ...

, Lentogesic in

South Africa South Africa, officially the Republic of South Africa (RSA), is the Southern Africa, southernmost country in Africa. Its Provinces of South Africa, nine provinces are bounded to the south by of coastline that stretches along the Atlantic O ...

, and Di-Antalvic in

France France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...

(unlike co-proxamol, which is an approved name, these are all brand names). Dextropropoxyphene is known under several synonyms, including: * Alpha-d-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol propionate * 2''S'',3''R'')-4-(Dimethylamino)-3- methyl-1,2-diphenylbutan-2-ylpropanoate * (+)-1,2-Diphenyl-2-propionoxy- 3-methyl-4-di-methylaminobutane * Desoxypropiophen

Uses

Analgesia

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

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...

, it is a weak

. However, dextropropoxyphene has one-third to one-half of the analgesic activity of codeine.

Restless legs syndrome

Dextropropoxyphene has been found to be helpful in relieving the symptoms of

restless legs syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...

Contraindications

Dextropropoxyphene is contraindicated in patients

allergic Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...

to paracetamol (acetaminophen) or dextropropoxyphene, and in

alcoholics Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World Hea ...

. It is not intended for use in patients who are prone to suicide, anxiety, panic, or addiction.

Side effects

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 Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

. Other side effects include: *Constipation *Itching *Drowsiness *Nausea *Sensorineural deafness

Pharmacology

Dextropropoxyphene acts as a mu-opioid receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

. It also acts as a potent, noncompetitive α₃β₄ neuronal

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. as well as a weak

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the drug action, action of the serotonin transporter (SERT). This in turn lea ...

Toxicity

Overdose is commonly broken into two categories -

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

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 Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

aspiration pneumonia Aspiration pneumonia is a type of lung infection that is due to a relatively large amount of material from the stomach or mouth entering the lungs. Signs and symptoms often include fever and cough of relatively rapid onset. Complications may incl ...

miosis Miosis, or myosis (), is excessive constriction of the pupil.Farlex medical dictionary
citing: ...

, and gastrointestinal effects seen in propoxyphene poisoning. It may also account for mood- or

thought In their most common sense, the terms thought and thinking refer to cognitive processes that can happen independently of sensory stimulation. Their most paradigmatic forms are judging, reasoning, concept formation, problem solving, and de ...

-altering effects. In the presence of amphetamine, propoxyphene overdose increases CNS stimulation and may cause fatal convulsive seizures. In addition, both propoxyphene and its metabolite norpropoxyphene have local

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into t ...

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 Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia and ventricular fibrillation. When used for local anae ...

. Local anesthetic activity appears to be responsible for the

arrhythmias Arrhythmias, also known as cardiac arrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – above 100 beats ...

and cardiovascular depression seen in propoxyphene poisoning. Both propoxyphene and norpropoxyphene are potent blockers of cardiac membrane

sodium channels Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels. Classification They are classified into 2 types: Function In e ...

, and are more potent than lidocaine,

quinidine Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...

, and

procainamide Procainamide (PCA) is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is a sodium channel blocker of cardiomyocytes; thus it is classified by the Vaughan Williams classification system as class Ia. ...

in this respect. 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 Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...

(i.e. cardiovascular depression), decreased

contractility Contractility refers to the ability for self- contraction, especially of the muscles or similar active biological tissue *Contractile ring in cytokinesis *Contractile vacuole *Muscle contraction **Myocardial contractility *See contractile cell fo ...

, and decreased

electrical conductivity Electrical resistivity (also called volume resistivity or specific electrical resistance) is a fundamental specific property of a material that measures its electrical resistance or how strongly it resists electric current. A low resistivity in ...

(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 Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two ...

. Widening of the QRS complex appears to be a result of a quinidine-like effect of propoxyphene, and

sodium bicarbonate Sodium bicarbonate ( IUPAC name: sodium hydrogencarbonate), commonly known as baking soda or bicarbonate of soda (or simply “bicarb” especially in the UK) is a chemical compound with the formula NaHCO3. It is a salt composed of a sodium cat ...

therapy appears to have a positive direct effect on the QRS dysrhythmia.

Seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s may result from either opioid or local anesthetic effects.

Pulmonary edema Pulmonary edema (British English: oedema), also known as pulmonary congestion, is excessive fluid accumulation in the tissue or air spaces (usually alveoli) of the lungs. This leads to impaired gas exchange, most often leading to shortness ...

may result from direct pulmonary toxicity,

neurogenic In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes t ...

anoxic Anoxia means a total depletion in the level of oxygen, an extreme form of hypoxia or "low oxygen". The terms anoxia and hypoxia are used in various contexts: * Anoxic waters, sea water, fresh water or groundwater that are depleted of dissolved ox ...

effects, or cardiovascular depression.

Balance disorder A balance disorder is a disturbance that causes an individual to feel unsteady, for example when standing or walking. It may be accompanied by feelings of giddiness, or wooziness, or having a sensation of movement, spinning, or floating. Equilibr ...

is possible, with risk of falls from standing height.

Available forms

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. Because of different

molar mass In chemistry, the molar mass () (sometimes called molecular weight or formula weight, but see related quantities for usage) of a chemical substance ( element or compound) is defined as the ratio between the mass () and the amount of substance ...

, 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.

Drug testing

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. 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 Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal sym ...

History

Dextropropoxyphene was successfully tested in 1954 as part of

US Navy The United States Navy (USN) is the naval warfare, maritime military branch, service branch of the United States Department of Defense. It is the world's most powerful navy with the largest Displacement (ship), displacement, at 4.5 millio ...

and

CIA The Central Intelligence Agency (CIA; ) is a civilian foreign intelligence service of the federal government of the United States tasked with advancing national security through collecting and analyzing intelligence from around the world and ...

-funded research on nonaddictive substitutes for

Use in organic synthesis

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.

Usage controversy and regulation

Dextropropoxyphene is subject to some controversy; while many

physician A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...

s prescribe it for a wide range of mildly to moderately painful symptoms, as well as for treatment of

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, many others refuse to prescribe it, citing limited effectiveness. In addition, the

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

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 Eli Lilly (July 8, 1838 – June 6, 1898) was a Union Army officer, pharmacist, chemist, and businessman who founded Eli Lilly and Company. Lilly enlisted in the Union Army during the American Civil War and recruited a company of men to ...

, 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 Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...

. Darvon was never withdrawn from the market, until recently, 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. 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.

Australia

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, but Aspen Pharma sought a review in the Administrative Appeals Tribunal which ruled in 2013 that the drugs could be sold under strict conditions.

Canada

On December 1, 2010, Health Canada and

Paladin Labs Knight Therapeutics Inc. is a Canadian public specialty pharmaceutical company based in Montreal, Quebec that focuses on acquiring or in-licensing innovative pharmaceutical products for the Canadian and select international markets. It is listed on ...

Inc. announced the voluntary recall and withdrawal of Darvon-N from the Canadian market and the discontinuation of sale of Darvon-N.

European Union

In November 2007, the

European Commission The European Commission (EC) is the primary Executive (government), executive arm of the European Union (EU). It operates as a cabinet government, with a number of European Commissioner, members of the Commission (directorial system, informall ...

requested the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(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 European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are Geography of the European Union, located primarily in Europe. The u ...

. 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 "

") was too small.

New Zealand

In February 2010,

Medsafe Medsafe, the New Zealand Medicines and Medical Devices Safety Authority, is the medical regulatory body run by the New Zealand Ministry of Health, administering the Medicines Act 1981 and Medicines Regulations 1984. Medsafe employs approximately ...

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

India

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.

Sweden

Sweden Sweden, formally the Kingdom of Sweden, is a Nordic countries, Nordic country located on the Scandinavian Peninsula in Northern Europe. It borders Norway to the west and north, and Finland to the east. At , Sweden is the largest Nordic count ...

, 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. Physicians had earlier been recommended to prescribe products with only dextropropoxyphene and not to patients with a history of

substance use disorder Substance use disorder (SUD) is the persistent use of drugs despite substantial harm and adverse consequences to self and others. Related terms include ''substance use problems'' and ''problematic drug or alcohol use''. Along with substance-ind ...

, 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

decision. 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 Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

, 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 Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

liver failure Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...

, and

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

. This toxicity with the combination of overdosed dextroproxyphene (with its CNS/

/vomit with risk for

, as well as

cardiotoxicity Cardiotoxicity is the occurrence of heart dysfunction as electric or muscle damage, resulting in heart toxicity. This can cause heart failure, arrhythmia, myocarditis, and cardiomyopathy in patients. Some effects are reversible, while in others, p ...

) and paracetamol-induced liver damage can result in death.

United Kingdom

In the United Kingdom, preparations containing only dextropropoxyphene were discontinued in 2004. In 2007, the

Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are accepta ...

removed the licence for co-proxamol, also called distalgesic. 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. The co-proxamol preparations available in the UK contained a subtherapeutic dose of paracetamol, 325 mg per tablet. 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 antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

s 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. 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 and on 17 January 2007. 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 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. 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 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. 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. 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.

United States

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 Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...

. A subsequent re-evaluation resulted in a July 2009 recommendation to strengthen the boxed warning for propoxyphene to reflect the risk of overdose. Dextropropoxyphene subsequently carried a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

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.

Because of potential for side effects, this drug is on the list for high-risk medications in the elderly. 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.

Tramadol Tramadol, sold under the brand name Tramal among others, is an opioid analgesic, pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release form ...

, 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.

In Popular Culture

In the

Stephen King Stephen Edwin King (born September 21, 1947) is an American author. Dubbed the "King of Horror", he is widely known for his horror novels and has also explored other genres, among them Thriller (genre), suspense, crime fiction, crime, scienc ...

short story collection ''

Night Shift The shift plan, rota or roster (esp. British) is the central component of a schedule (workplace), shift schedule in shift work. The schedule includes considerations of shift overlap, shift change times and alignment with the clock, vacation, train ...

'', the final story of the book, "

The Woman in the Room "The Woman in the Room" is a short story by Stephen King, first published in King's 1978 collection ''Night Shift''. It was adapted as a short film of the same name in 1983, directed by Frank Darabont at the beginning of his career. Plot summary ...

", tells a tale in which the main character contemplates and then finally performs a mercy killing using a drug called "Darvon Complex." In his 1976 song "My Head Hurts My Feet Stink and I Don't Love Jesus" Jimmy Buffett references taking a Darvon to relieve his hangover.

Use by right-to-die societies

High toxicity and relatively easy availability made propoxyphene a drug of choice for right-to-die societies. It is listed in Dr.

Philip Nitschke Philip Haig Nitschke (; born 8 August 1947) is an Australian humanist, author, former physician, and founder and director of the pro-euthanasia group Exit International. He campaigned successfully to have a legal euthanasia law passed in Austral ...

's ''

The Peaceful Pill Handbook ''The Peaceful Pill Handbook'' is a book that provides information on assisted suicide and voluntary euthanasia. Written by the Australian doctor Philip Nitschke and lawyer Fiona Stewart, it was originally published in the U.S. in 2006. A Germ ...

'' and Dr. Pieter Admiraal's ''Guide to a Humane Self-Chosen Death''. "With the withdrawal of the

barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...

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."

References

{{Navboxes , title =

Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

, titlestyle = background:#ccccff , list1 = {{Ion channel modulators {{Ionotropic glutamate receptor modulators {{Monoamine reuptake inhibitors {{Nicotinic acetylcholine receptor modulators {{Opioid receptor modulators Synthetic opioids Dimethylamino compounds Antitussives Combination analgesics Drugs developed by Eli Lilly and Company Hepatotoxins HERG blocker Mu-opioid receptor agonists NMDA receptor antagonists Propionate esters Withdrawn drugs Potassium channel blockers