Propoxyphene ( a withdrawal drugs)

Propoxyphene or known as Darvon is a pain reliever (analgesic) that works as effective as narcotics analgesic like morphine yet lower in abuse liability^{1; 2}. It first introduced in 1957 and became popularly prescribed drug along with aspirin to soothe mild to moderate pain in the patients. In 2004 it was the 12^th bestselling generic drug in the US market ^{1; 3; 4}. Mostly propoxyphene was prescribed together with a nonsteroidal non-inflammatory drug (NSAIDs) like aspirin to enhance the analgesic effect.  Both possesses similar efficacy through a different route of a mechanism. Aspirin inhibits the chemoreceptors in the peripheral nervous system while propoxyphene affects the central nervous system^{3; 5}. 

As a group of narcotic drugs, propoxyphene binding in the opioid receptor, inhibit pain transmission. It is acted as an agonist of µ₁ (mu) opioid receptor and some κ (kappa) receptor, exerts an analgesic transmission. However, it also binds to µ₂ opioid receptor that leads to side effects⁶.

 

Fig1.

An illustration of opioid receptors and NMDA receptor ⁷.

Propoxyphene relieves the pain after 2 to 2.5 h with half-life time is between 6 to 12 h. However, the metabolite form of propoxyphene, which is nor-propoxyphene (the primary product) is eliminated after 30 to 36 h. The nor-propoxyphene has resulted from N-demethylation route by the CYP3A4 enzyme as the primary pathways. It is eliminated through renal system, excreted into urine. Ester hydrolysis and N-acetylated products were also found in the system as the minor route ^{4; 9; 10; 11}.

Propoxyphene is a painkiller drug that works on central nervous system depressant. The consumption of this drug is dangerous if it mixed with alcohol. Since alcohol also works as a central nervous depressant, the malfunction of signaling cascade could occur. It also could shut down the respiratory system, lead to immediate death. Mostly life-threatening case in elderly was caused by this action. Grapefruit is another dangerous food when propoxyphene is being consumed. Grapefruit possesses an ability to improve the activity of the CYP3A4 enzyme, increasing the concentration of metabolite product which is nor-propoxyphene. The excessive nor-propoxyphene will induce toxicity because it is eliminated after 30-30 h in the body system^{4; 12}.

Propoxyphene considered to be weak opioid drug since it is low in the binding affinity as well as its selectivity. This condition leading to unintended activation receptor which resulting side effects such as being sleepy and lethargic, delusional disorder and other severe conditions like coma⁸. Another drawback of this drug also caused by its active metabolite compound, nor-propoxyphene. Because of the high clearance rates (eliminated after 30-36 h), accumulation of this molecule could happen in the central nervous system (CNS), cardiovascular system and respiratory system. It triggered many adverse effects such as ataxia, cardiotoxicity, visual disturbance, seizures, euphoria, and many others, even death. Even though it prescribed in therapeutic doses, the life-threatening effect still occurs ^{6; 13}.

There were many death cases related to propoxyphene products such as Darvon and Darvocet (propoxyphene and acetaminophen). In the United States, around 2110 accidental death reported since 1981 to 1999, while in the United Kingdom (England and Wales), approximately 300-400 per year citizens found to be overdose from the drugs. Because of the safety risk issues, the UK Government started to withdraw the drug from UK markets in 2005, followed by the European Union in 2008^{4; 14}. 

In the United States, the withdrawal had been proposed since 1978 by The Health Research Group (HRG) of Public Citizen. However, the FDA rejected the petition because the side effects probably occur due to the producer negligence in the dose which was higher than FDA’s recommendation. But, the drug abused and health issues keep appeared. A study in the elder showed that the consumers had probability 2.4 times higher than non-consumer to treated in the emergency room or died. In total, there were 7109 deaths cases found in the US (1981-2006). Since then, many types of research were conducted to review the safety and the efficacy of the propoxyphene products. In general, the propoxyphene drug exerted toxicity in the body system. The analgesic effect mostly came from the combination compound that mixed with the propoxyphene like aspirin and acetaminophen. Since the drawbacks outweighed the benefits, the citizen of United States once again filled out a petition in 2006. After reviewing all the safety issues, FDA then announced the withdrawal of propoxyphene from US market. The withdrawal announcement was effective in decrease the propoxyphene user. To overcome the addiction effect, the patients were prescribed into another opioid drug that much safer^{1; 4; 6; 14; 15; 16; 17}.  

To conclude, propoxyphene that sells under the name Darvon was popular to relief pain. However, the side effects outweigh its medicinal properties. There were many toxicities and life-threatening cases which made the drug withdrawn from the market.