Dextropropoxyphene is an
analgesic
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
in the
opioid category, patented in 1955 and manufactured by
Eli Lilly and Company
Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
. It is an
optical isomer of
levopropoxyphene
Levopropoxyphene is an antitussive. It is an optical isomer of dextropropoxyphene. The racemic mixture is called propoxyphene. Only the dextro-isomer (dextropropoxyphene) has an analgesic effect; the levo-isomer appears to exert only an antitussi ...
. It is intended to treat mild pain and also has
antitussive (cough suppressant) and
local anaesthetic
A local anesthetic (LA) is a medication that causes absence of pain sensation. In the context of surgery, a local anesthetic creates an absence of pain in a specific location of the body without a loss of consciousness, as opposed to a general an ...
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, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
. 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 Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...
, Lentogesic in South Africa, and Di-Antalvic in France (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, 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 ...
, is a weak opioid, known to cause dependency among recreational users. Codeine is more commonly used; however, as codeine is, in essence, a prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
that requires '' in vivo'' metabolism (to morphine via demethylation) for efficacy, it is ineffective for some individuals with the "poor metabolizer" genotype of the liver cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzyme CYP2D6. In people with this low-function isoform, 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
Dextropropoxyphene has been found to be helpful in relieving the symptoms of restless legs syndrome.
Opioid withdrawal
In pure form, dextropropoxyphene is commonly used to ease the withdrawal
Withdrawal means "an act of taking out" and may refer to:
* Anchoresis (withdrawal from the world for religious or ethical reasons)
* ''Coitus interruptus'' (the withdrawal method)
* Drug withdrawal
* Social withdrawal
* Taking of money from a ban ...
symptoms in people addicted to opioids. Being very weak in comparison to commonly used opioids, dextropropoxyphene can only act as a "partial" substitute. It does not have much effect on mental cravings, but it can be effective in alleviating physical withdrawal effects, such as muscle cramps.
Contraindications
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.
Side effects
*Constipation
*Itching
*Drowsiness
*Sore throat
*Impaired alertness
*Confusion
*Serious or fatal heart rhythms
*Nausea
Pharmacology
Dextropropoxyphene acts as a mu-opioid receptor agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
. It also acts as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
, as well as a weak serotonin reuptake inhibitor.
Toxicity
Overdose is commonly broken into two categories - liver toxicity (from paracetamol poisoning
Paracetamol poisoning, also known as acetaminophen poisoning, is caused by excessive use of the medication paracetamol (acetaminophen). Most people have few or non-specific symptoms in the first 24 hours following overdose. These include f ...
) and dextropropoxyphene overdose.
An overdose of dextropropoxyphene may lead to various systemic effects. Excessive opioid receptor stimulation is responsible for the CNS depression
Central nervous system (CNS) depression is a physiological state that can result in a decreased rate of breathing, decreased heart rate, and loss of consciousness possibly leading to coma or death.
It is the result of inhibited or suppressed brai ...
, 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 (hypercapnia ...
, aspiration pneumonia, , 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 conscious cognitive processes that can happen independently of sensory stimulation. Their most paradigmatic forms are judging, reasoning, concept formation, problem solving, a ...
-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
Norpropoxyphene is a major metabolite of the opioid analgesic drug dextropropoxyphene, and is responsible for many of the side effects associated with use of this drug, especially the unusual toxicity seen during dextropropoxyphene overdose. It h ...
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
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. When used for local anaesthesia or in nerve blocks, lidoca ...
.[Nickander ''et al.'', 1984] 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
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 and can be classified according to the trigger that opens the channel ...
, and are more potent than lidocaine, quinidine, and procainamide in this respect.[Holland & Steinberg, 1979] 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
Electrical resistivity (also called specific electrical resistance or volume resistivity) is a fundamental property of a material that measures how strongly it resists electric current. A low resistivity indicates a material that readily allow ...
(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.[Strom ''et al.'', 1985b][Bredgaard, Sorensen ''et al.'', 1984] 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, is a chemical compound with the formula NaHCO3. It is a salt composed of a sodium cation ( Na+) and a bicarbonate anion ( HCO3−) ...
therapy appears to have a positive direct effect on the QRS dysrhythmia.[Stork ''et al.'', 1995]
Seizures may result from either opioid or local anesthetic effects.[ Pulmonary edema may result from direct ]pulmonary toxicity Pulmonary toxicity is the medical name for side effects on the lungs.
Although most cases of pulmonary toxicity in medicine are due to side effects of medicinal drugs, many cases can be due to side effects of radiation (radiotherapy). Other (non-me ...
, neurogenic/ anoxic effects, or cardiovascular depression.[
Balance disorder 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. Napsylate salt (the salt of naphthalenesulfonic 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 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 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.
History
Dextropropoxyphene was successfully tested in 1954 as part of US Navy and CIA
The Central Intelligence Agency (CIA ), known informally as the Agency and historically as the Company, is a civilian intelligence agency, foreign intelligence service of the federal government of the United States, officially tasked with gat ...
-funded research on nonaddictive substitutes for 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 ...
.
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 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
Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and s ...
. 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.["FDA pulls common pain med off the market"](_blank)
November 19, 2010. CNN.
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 drug, pharmaceutical company based in Montreal, Quebec that focuses on acquiring or in-licensing innovative pharmaceutical products for the Canadian and select international mar ...
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 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 medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(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.
New Zealand
In February 2010, Medsafe announced Paradex
Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive (cough suppressant) ...
and Capadex
Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive (cough suppressant ...
(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
In Sweden
Sweden, formally the Kingdom of Sweden,The United Nations Group of Experts on Geographical Names states that the country's formal name is the Kingdom of SwedenUNGEGN World Geographical Names, Sweden./ref> is a Nordic country located on ...
, 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 (including alcohol) despite substantial harm and adverse consequences as a result of their use. Substance use disorders are characterized by an array of mental/emotional, physical, and ...
, 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.
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, liver failure, and necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
. This toxicity with the combination of overdosed dextroproxyphene (with its CNS/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 (hypercapnia ...
/vomit with risk for aspiration pneumonia, as well as cardiotoxicity
Cardiotoxicity is the occurrence of heart dysfunction as electric or muscle damage, resulting in heart toxicity. The heart becomes weaker and is not as efficient in pumping blood. Cardiotoxicity may be caused by chemotherapy (a usual example is th ...
) 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 acceptably ...
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.["Withdrawal of co-proxamol products and interim updated prescribing information"](_blank)
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 acceptably ...
(MHRA). 31 January 2005. Retrieved August 28, 2009. Prescribing authorities, such as the Royal College of General Practitioners, unanimously recommended withdrawal, while patients who responded to the agency's request for information tended to want to continue treatment.
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, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and we ...
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, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
. 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 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 Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an h ...
, 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.
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's ''The Peaceful Pill Handbook
''The Peaceful Pill Handbook'' is a book setting out 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 Germa ...
'' and Dr. Pieter Admiraal's ''Guide to a Humane Self-Chosen Death''. "With the withdrawal of the barbiturate
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...
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."
See also
* Ketobemidone
* Meperidine
References
{{Navboxes
, title = Pharmacodynamics
, 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 drugs
Eli Lilly and Company brands
Hepatotoxins
Mu-opioid receptor agonists
NMDA receptor antagonists
Propionate esters
Withdrawn drugs
Potassium channel blockers