Case study about a drug that was withdrawn after approval due to toxicity

Propoxyphene
1. Introduction
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 12th 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 different
route of a mechanism. Aspirin inhibit the chemoreceptors in the peripheral nervous system while
propoxyphene affects the central nervous system3; 5.
2. Mode of action
As a group of narcotic drugs, propoxyphene binding in the opioid receptor, inhibit pain
transmission. It is acted as an agonist of µ 1 (mu) opioid receptor and some κ (kappa) receptor,
exerts an analgesic transmission. However, it also binds to µ 2 opioid receptor that leads to side
effects6.

Fig1.
An illustration of opioid receptors and NMDA receptor 7.
Propoxyphene also found to bind to another receptor called NMDA (N-Methyl-D-Aspartate)
receptor as its antagonist. This receptor is associated with various pain managements in the
neural area. Hence, the activation of this receptor will improve the opioid analgesia8.
3. Metabolism

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 major
product) is eliminated after 30 to 36 h. The nor-propoxyphene has resulted from N-
demethylation route by the CYP3A4 enzyme as the major pathways. It is eliminated
through renal system, excreted into urine. Ester hydrolysis and N-acetylated products
were found also in the system as the minor route 4; 9; 10; 11.

Fig 2
N-demethylation of propoxyphene9
4. Interaction drug

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 system4; 12.

5. Side effect and withdrawn process

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 20084; 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 safer1; 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 medical properties. There were many toxicities and life-
threatening cases which made the drug withdrawn from the market.