Some facts of Dextropropoxyphen - A component of Spasmo-proxyvon (SP)

Dr Diamond *

1. Description:

Dextropropoxyphene is classified as an opioid analgesic and is used to treat mild to moderate pain. It can be used to ease pain before, during and after an operation. It is often combined with Acetaminophen and sold in several countries (note: In some countries, compounds containing Dextropropoxyphene are available only with a valid doctor's prescription). Dextropropoxyphene is derived from a much stronger opiate agonist called Methadone. It is approximately 1/2 to 2/3 as potent as Codeine.

Propoxyphene refers to a racemic mixture of both Dextro-Propoxyphene and its optical isomer Levo-Propoxyphene. Dextro-Propoxyphene possesses only mild analgesic activity but no anti-tussive activity. However, with Levo-Propoxyphene, the converse is true (i.e. it possesses only anti-tussive activity but no analgesic activity).

In the United States, Dextropropoxyphene HCI is available as a prescription with Acetaminophen in ratio anywhere from 30 mg/600 mg to 60 mg, 325. mg respectively. These are usually named "Darvocet," "Darvin," or "Darvon." In Australia, dextropoxyphene is available on prescription, both as a combined product (32.5 mg dextropropoxyphene per 325 mg acetaminophen) known as either "Di-gesic", "Capadex", or "Paradex" and in pure form (100 mg capsules) known as "Doloxene". Dextropropoxyphene is marketed in Europe as "Abalgin" amongst other names.

In India, Dextro-Propoxyphene is found in a number of pharmaceutical preparations. The most common are

Brand name ------- Active Ingredients
- Diclofenac Sodium
Buta-PROXYVON - 32.5 mg Dextropropoxyphene HCI
- 400 mg Acetaminophen
PROXYVON - 65 mg Dextropropoxyphene HCI
400 mg Acetaminophen
- 65 mg Dextropropoxyphene HCI
SPASMO- - 400 mg Acetaminophen
PROXYVON 10 mg Dicyclomine

Note: In parts of Southern India, it has come to our attention that the key ingredient in these preparations has changed from bextropropoxyphene HCI to Dextropropoxyphene Napsylate. There are key differences between these formulations:

• First, the Napsylate salt form is WATER-IN SOLUBLE. Hence, it cannot be abused by the parenteral route (i.e. by injection);
• Second, approximately 100 mg of Dextropro poxyphene Napsylate is equivalent to 65 mg of Dextropropoxyphene Hql.
• Third, the onset of action of the Napsylate salt is slightly longer (about an hour) than that of the HCI salt.

2. INDICATIONS:

Analgesia

Dextropropoxyphene, like Codeine, is classified as a "week" opioid. Codeine is more commonly used, however some individuals (approximately 10·20% of the Caucasian population) are unable to metabolize it, due to poor functioning of a hepatic enzyme called CYP2D6. It is in these people that dextropropoxyphene is particularly useful, and does not require CYP2D6 (as it is metabolism is via CYP3A4).

The maximum doses for the constituents of Spasmo Proxyvon (constituents shown above) are as follows:

• Acetaminophen: 2-4 grams/day
• Dextro-Propoxyphene HCI : 390 mg/day
• Dextro-Propoxyphene Napsylate : 600 mg/day
• Dicyclomine : No available safety data for dos es above 80 mg/day

Opioid Withdrawal

In pure form, Dextropropoxyphene is commonly used to ease the withdrawal symptoms in people addicted to opioids. However, being very weak in comparison to those opioids which are commonly abused, dextropropoxyphene can only act as a "partial" substitute. It does not have much effect or mental cravings; however it can be effective in alleviating physical withdrawal effects such as muscle cramps.

Dextropropoxyphene is subject to some controversy: whilst many physicians prescribe it for a wide range of mild to moderately painful symptoms as well as in treatment of diarrhoea, many others refuse to prescribe it, citing its highly addictive nature and limited effectiveness (some studies show it to be no more effective as a painkiller than aspirin).

The therapeutic index of dextropoxyphene 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 acetminophen toxicity. So far, Australia has declined to follow suit, and opted to allow pure dextropropoxyphene to remain available by prescription.

3. PHARMACOKETICS :

Dextropropoxyphene (DPP) has a 1/2 life of 6 to 12 hours. However, its metabolite, norpropoxyphene (NPP) has a 1/2 life of 30 to 36 hours. After oral ingestion, onset of effects is usually 1 hour, with peak plasma concentrations achieved within 2 - 21/2 hours. Repeated doses (at intervals of 6 hrs.), lead to increasing plasma concentrations, eventually reaching a plateau at/after the 9th dose (at 48 hrs.).

It is worth knowing that due to extensive first-pass metabolism of DPP, the plasma concentrations after a single dose may be four times lower than those found in steady state (achieved with regular dosing at 6 hr. intervals). Also, with repeated dosing, it takes longer for the metabolite to be eliminated. On the whole, the metabolism of DPP takes a lot longer than that of morphine.

4. ADVERSE EFFECTS:

Side effects ( just as with other opiates) include:

• impairment of mental performance.
• euphoria.
• drowsiness.
• lethargy.
• blurred vision.
• miosis (constriction of pupils)
• decreased appetite.
• inhibition of the cough reflex (antitussive effect)
• respiratory depression.
• constipation.

Overdose is commonly broken into two categories: liver toxicity (from acetaminophen poisoning) and dextropropoxyphene overdose. Many users experience toxic effects from the acetaminophen in pursuit of the endnessly-increasing dose required to achieve euphoria. They suffer acute liver toxicity, which causes severe stomach pain, 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 indocaine.

Both propoxyphene and norpropoxyphene also have direct cardiac effects which include decreased heart rate, decreased contractibility, and decreased electrical conductity (i.e. increase 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.

Both propoxyphene and norpropoxyphene are potent blockers of cardiac membrane sodium channels and are more potent than lidocaine, quinidine, and procainamide in this respect. They (propoxyphene and nor-propoxyphene) appear to have the characteristics of a Vaughn Williams Class IC antiarrhythmic.

5. TOXICOLOGICAL MECHANISM:

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. Local anesthetic activity appears to be responsible for the arrhythmias and cardiovascular depression seen in propoxyphene poisoning. 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.

Seizures may result from either opioid or local anesthetic effects. Pulmonary edema may result from direct pulmonary toxicity, neurogenic/anoxic effects, or cardiovascular depression.

6. RECREATIONAL USE:

The general consensus amongst recreational drug-users is that Dextropropoxyphene, when injected, products an amazing rush, on par with heroin. However, there is very little euphoria that occurs after the rush, so users tend to keep on injecting on an hourly basis to continue experiencing the rush throughout the day.

This is in direct contrast with injecting Methadone, where IDUs (Injection Drug Users) describe little to no "rush" upon intravenous administration, but a tremendous euphoria that lasts for quite a long time (in comparison with most shorter-acting opiates like Heroine or Morphine)

7. Question/Answer:

How can I get rid of an addiction to Spasmo-Proxyvon (SP)
Q. I am addicted to SP for the past 2 years. I want to stop taking this drug. Please suggest a few tips. I had tried to stop for about 16 days' during which I could not sleep and I had pain in my legs. The food also tasted bad (question from an SP addict.)
A. Spasmo Proxyvon contains dextropropoxyphene which is a weak opiod (opium-like) agent. You should gradually reduce the dose slowly but steadily and surely over the next few weeks. With a strong will power, it is not difficult. Please keep in mind that the situation will become worse if you do not stop now and you may need to go to a de-addiction centre.

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* Dr Diamond wrote this article for Hueiyen Lanpao (English Edition). The writer is M.O., ART Unit, JN Hospital and his article is Courtesy: Hakshel, A quarterly journal). This was webcasted on January 06th , 2010.

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