A- dextro Propoxyphene {see structure below }

B- levo Propoxyphene {see structure below }

About Propoxyphene :

Propoxyphene Is a synthetic analgesic that was approved by the FDA in 1957 . It belongs to the opiate category, Propoxyphene is classified as mild to moderate Analgesic drug. It is structurally more related to Methadone than to Morphine, Compared with Codeine, Propoxyphene is 1/2 To 2/3 as potent as an analgesic . It is available as a HCl or as napsylate. [Each 65 mg of the HCl form is equivalent to 100 mg of the napsylate form ] it's use is reduced due to the release of more effective compounds and due to the difficulty to maintain it's over dose , It has no antipyretic effect and little or no anti tussive.

Pharmacodynamics & Mechanism of action :

It acts as an agonist at m - receptors and produces analgesia to the CNS in addition to other Morphine like effects. Stimulation of the opiate receptors lead to the reduction of the neurotransmitter release. And this is through the following mechanisms :

1. Changing Calcium ion mobilization .
2. Inhibition of Adenylate Cyclase .
3. changes in Potassium ion conductance .

Propoxyphene alters pain feeling ( perception of pain ) in the CNS and has no effect on the Afferent nerve endings .

Pharmacokinetics :

• Absorption

The duodenum ; the HCl salt absorbed faster than the napsylate due to greater water solubility .

• Metabolism

Propoxyphene undergoes extensive First pass effect (30% - 70%).

1/4 of the dose is metabolized to the active NorPropoxyphene by oxidative N- demethylation .

• Analgesia is achieved within 20 to 60 minutes and PPC is reached after 2 - 3 hours .

• Distribution

Propoxyphene reaches the CSF , and crosses the placenta

• Protein binding

about 80 % of Propoxyphene is protein bound .

• Excretion

Mostly in the Urine for the drug and it's active metabolite, Propoxyphene is also excreted in Milk .

• t½ 14.6 hours.

NorPropoxyphene has local anesthetic effect but has fewer CNS depressant effect than the parent drug .

Indications :

dextro Propoxyphene is indicated for relief of Pain ( Mild to moderate pain ) and it is not effective against deep pain, it's effect on mild pain is not more than that of Aspirin ; so the two can be combined to achieve an additive effect .

Besides being an Analgesic ; dextroPropoxyphene has a depressant effect and a very weak anti tussive effect - not strong enough - and can cause euphoria at high doses .

Side effects :

A > Most common side effects include : Dizziness , Drowsiness sedation , Nausea and Vomiting .

B > Other side effects : Constipation , Abdominal pain, Rash, jaundice, Headache, Weakness, euphoria, Dysphoria, arrhythmia, Hypotension (due to membrane-stabilizing or Quinidine like effect) and Respiratory depression.

Contraindications & Precautions :

1. Cardiac diseases . 6. Pulmonary disorders ( asthma , COPD,...,)
2. Infectious Diarrhea . 7. Renal disease and/or Hepatic disease.
3. Elderly . 8. History of previous Substance abuse.
4. Head trauma . 9. Surgery .
5. Pregnancy . 10. Hypersensitivity to Aspirin , Acetaminophen, Caffeine

• since Propoxyphene has can cause Arrhythmia ; it shouldn't be given to patients with heart diseases .
• Patients suffering from diarrhea secondary to poising or infection should not take Propoxyphene because it may slow the removal of the infecting agent or toxic material .
• The elderly are more susceptible to adverse reactions and so dose should be reduced
• Patients with head trauma and with increased intra cranial pressure should not take Propoxyphene because Hypoventilation will lead to increased CSF pressure and thereby increase the injury.
• Propoxyphene can cross the placenta ; therefore pregnant women are not to take it , and this applies to Nursing mothers as Propoxyphene is excreted in Milk << Propoxyphene is classified as pregnancy category C >>.
• Respiratory depression that may be caused by the drug can worsen the respiratory disorder .
• Generally the dose should be reduced to patients with renal problems to prevent accumulation of the drug to toxic levels .
• Hepatotoxicity : Drug induced hepatotoxicity takes a number from 1to 4 in which :

1 = Cytotoxic , Intrinsic hepatotoxin.

2 = Cytotoxic , Idiosyncracy.

3 = Cholestatic , Intrinsic hepatotoxin.

4 = Cholestatic , Idiosyncracy.

Propoxyphene is classified as 4, Only a few cases of Propoxyphene induced Cholestasis have been reported, but comments in the litretere suggest that more have been observed .

• Patients with a history of substance abuse should be given the drug with caution.
• Propoxyphene can cause biliary tract spasm & should be used with caution with patients undergoing Biliary tract surgery .
• Hyper sensitivity to Aspirin , acetaminophen , Caffeine because many formulation of Propoxyphene contain these ingredients .

Drug Interactions :

1. MAO inhibitors , Anti depressants .
2. Anti diarrheas .
3. Anti hyper tensive .
4. CNS depressants : Benzodiazepines, barbiturates, H₁blockers, Alcohol.
5. Naloxone and Naltrexone .
6. Skeletal muscle relaxants .
7. Warfarin.
8. Carbamazepine.
9. Cimetidine.

• Concurrent use of anti diarrheals & Propoxyphene can lead to sever constipation .
• Anti hyper tensive drugs can produce and exaggerated response when used with Propoxyphene .
• Concomitant use of Propoxyphene with other CNS depressants can potentiate the effect of respiratory depression caused by Propoxyphene .
• Naloxone and Naltrexone oppose and antagonize Propoxyphene so if a patient is an addict , they will cause acute withdrawal symptoms.
• Orphanedrine used with Propoxyphene can lead to Confusion , Anxiety and tremors .
• Warfarin's effect can be increased when taking Propoxyphene .
• Use of Carbamazepine with Propoxyphene may cause blood concentrations of Carbamazepine to increase and can lead to dizziness, shakey movements, and Nausea.
• Cimetidine, when used with opiate analgesics can cause confusion, apnea, disorientation, or seizures due to respiratory and impaired CNS function .

dextro Propoxyphene preparations :

1. dextro Propoxyphene HCl

(2 S,3 R) (+)-4(Dimethylamino)-3-methyl-1,2-diphenyl-2-butanol propionate hydrochloride .

C₂₂H₂₉NO₂ .HCl = 375.9

It is a white, bitter crystalline powder .

Solubility : in water freely soluble

in Alcohol soluble

in Chloroform Soluble.

In Acetone Soluble .

in benzene practically insoluble .

in ether practically insoluble .

• It is able to suppress Morphine abstinence syndrome in addicts .

2. dextroPropoxyphene Napsylate,USP

(+)- a - 4-Dimethylamino-3-methyl-1,2-diphenyl-2-butanol propionate (ester) 2-naphthylenesulfonate (salt).

Solubility : very slightly soluble in water , Soluble in alcohol, chloroform, and acetone .

• It is claimed to be less addictable than the HCl form as it has low solubility in water and therefore can not be injected in the body and upon oral administration gives a slower , lower peak plasma Concentration .
• Hopes were build on this drug to be used instead of Methadone for treatment of addicts in the withdrawal period .
• This Intended use was limited due to the toxicity of this drug at higher Concentrations .

Dosage :

Adults

• Propoxyphene HCl : 65 mg every 3 - 4 hours Maximum dose should not exceed 390 mg / day .

• Propoxyphene Napsylate : 100 mg every 4 hours Maximum dose should not exceed 600 mg / day .

Adults with Impaired Renal function

If Creatinine clearance is < 10 ml /min. use is not recommended.

Adults with Impaired Hepatic function

Reduced dosage is recommended .

Safe & effective use in infants and Children has not been established

Propoxyphene is a prescription only drug and must not be given with out prescription .

This control imposed on the dispensing of this drug is due to the fear of over dose more than the fear of addiction , because this drug can cause addiction but not strongly ( it has low addiction properties ) but the fear is from over dose toxicity either due to a mistake or unawareance of the patient ( taking more dose to reduce the pain ) or intended increase in dose to cause Euphoria . Either way the drug can reach toxic levels and cause death .

In fact ; Propoxyphene is responsible for many cases of death.

For example "during epidemic abuse of dextroPropoxyphene among American solders 13 died ( Pulmonary edema was the main finding at post mortem . Respiratory arrest and psychotic reactions also occurred, 7 patients became dependent on the intravenous use of the drug , Abscesses, cellulitis, thrombophlebitis, or sclerosis of the veins developed within 6 to 12 weeks despite the use of sterile vehicles and techniques . Withdrawal symptoms were mild "

Treatment of Propoxyphene dependence

Treatment of dextro Propoxyphene dependence in a 41 year old woman who had a history of multiple drug abuse consisted of withdrawing dextro Propoxyphene and giving methadone on a reducing scale for 10 days .

Many reports emphasize the rapidity with which death occurs; death within an hour of overdose is considered to be uncommon. Dextro Propoxyphene infections are painful and have a very destructive effect on the soft tissue and veins .

Treatment of over dose and Adverse effects

• Rapid treatment of overdose with Naloxone .
• Help Respiration .
• Giving Activated Charchol .
• Convulsions may be controlled with Diazepam 5-10 mg I.V .
• Because many preparations of Propoxyphene contain Paracetamol; so we must put in mind that there is also an Acetaminophen poisoning and we must control and Manage that ( e.g. Giving Methionine ,...,).
• Also we must put in mind that there is also Aspirin poisoning as many Propoxyphene preparations are formulated with Aspirin .

Note : Dialysis has little effect in Over dose management .

Never Use stimulants , Stimulants can increase the convulsions.

Identifying the over dose :

Naloxone not only helps antagonize Propoxyphene ; It also helps us know if the symptoms are really due to Propoxyphene poisoning or not . If The patient does not respond to Three doses of 400 mg of Naloxone then the condition is probably due to another sedative drug , alcohol, or even Cerebral anoxia .

There is also the chance of having liver necrosis due to the over dose of Paracetamol associated with the Propoxyphene .

Other information

In patients who took lethal doses of the drug , It was found that the lung & liver concentration of the drug was 10 - 20 times more than that of the blood indicating that there might be a limit in the concentration of Propoxyphene that can stay in the blood . Indeed this limit is about 10 mg / ml , And the lung and the liver and Kidney can accumulate much more .

Labels & Patient information :

!!! CAUTION !!! Federal law prohibits the transfer of these medication to any person other than the patient for whom it was prescribed .

Take exactly as directed .

Take with food or milk .

Avoid alcohol .

ORAL LIQUID :

Shake well before use , Measure the dose accurately . Your Pharmacist can provide you with a specially marked measuring device. If desired; you may mix the dose in water or fruit juice just before tanking to improve the taste

This medication may be habit forming .

This medication may cause dizziness or drowsiness and decreased mental alertness.

This medication may impair the ability to drive or operate machinery.

Take exactly as directed by your doctor to reduce the chance of becoming dependent .

Avoid alcohol : alcohol increases the risk of severe drowsiness , dizziness, and confusion . It is not safe to drink alcohol while taking this medication because it can cause you to stop breathing.

If you have been instructed to take Propoxyphene on a regular schedule for pain, take missed doses as soon as possible after the dose was due. Do not take if it is nearly time for your next dose; Do not take double doses; and Do not take extra doses. Consult your doctor or Pharmacist if you need help adjusting your dosing schedule.

Propoxyphene is classified as Schedule IV prescription must be rewritten after 6 months or 5 Refills.

Preparations of dextro Propoxyphene :

1. dextro Propoxyphene Capsules : contain Propoxyphene Napsylate (B.P)
2. Propoxyphene HCl and Acetaminophen Tablets . (U.S.P)
3. Propoxyphene HCl and APC Capsules : Contain Propoxyphene HCl + Phenacitin + caffeine + Aspirin . (U.S.P)
4. Propoxyphene HCl capsules . (U.S.P)
5. Propoxyphene Napsylate and Acetaminophen Tablets . (U.S.P)
6. Propoxyphene Napsylate and Aspirin Tablets . (U.S.P)
7. Propoxyphene Napsylate Oral suspension . (U.S.P)
8. Propoxyphene Napsylate Tablets . (U.S.P)

Trade names for dextro Propoxyphene

Darvon^®, Darvon - N^®, Cosalgesic^®, Dextrogesic^®, Distalgesic^®, Dolasan ^®, Doloxene^® , Napsalgesic Tablets^® , Algaphan^® , Depronal^®

also Dolostop^® is the Jordanian drug produced by HIKMA and it contains dextro Propoxyphene Napsylate 50 gm and Acetaminophen 325 gm .

Dolostop Forte^® contains dextro Propoxyphene Napsylate 100gm and Acetaminophen 325 gm .

Physical describtion and costs :

*Darvon - N tablets , light yellow, oval ,

black lettering " Lilly DARVON N 100"

* DARVON- N SUSPENSION

Available as 10 mg/ml Propoxyphene napsylate in 480 ml bottles.

Costs : 65 mg HCl PO qid : is less than $10.

100 mg Napsylate PO qid : $50 .

Dolostop 20 capsules 0.35 Jordainian Dinar.

Dolostop forte 20 capsules 0.42 J.D .

levoPropoxyphene is a stereo isomer of dextro Propoxyphene , It has no Analgesic effects but has an Anti tussive effect , of course this Anti tussive effect is not as strong as that of Codeine; but it has an advantage that it does not Cause dependence.

50 to 100 mg of levo Propoxyphene are equal to 15 mg of Codeine.

the Dose of levo Propoxyphene is 50 - 100 mg every 4 hours. The most common side effect of levo Propoxyphene is Sedation which is not related to it's opiod like structure . levo Propoxyphene is used as an anti tussive for dry non productive cough . One thing worth to mention is that the Trade name of levo Propoxyphene is Novrad® which is Darvon® spelled backwards .

Propoxyphene; a few words to remember

as I conclude this report on Propoxyphene there are few things I'd like to mention . Propoxyphene is a methadone like opiate that is used as a Mild to moderate Analgesic . It has some addiction properties, though low; but still present . the benefits and advantages of Propoxyphene are overcome by it's toxicity ,So Using this drug should be limited due to it's Toxic effects . so It is not a good idea to prescribe this drug except if there is Absolute need for it .

1. Alfonso R Gennaro, Remington's Pharmaceutical Sciences ,Mack publishing company 17^th edition; Easton; Pennsylvania,1985 .

1. Bertram G. Katzung , Basic & Clinical Pharmacology ; 5^th edition, Appleton&Lange press; 1992 .
   
2. CCM MIDDLE EAST s.a.r.l., Middle east medical Index , 17^th edition Beirut, Lebanon .
   
3. LAURENCE & P. N. BENNETT , Clinical Pharmacology ; 7^thedition; 1992 .
   
4. Jaime N. Delgado and William A. Rmers, Wilson and Gisvold's Text book of Organic , Medicinal , and Pharmaceutical Chemistry . 9^th Edition , J.B. Lippincott Company; 1991.
   

1. James E. F. Reynolds , MARTINDALE the extra Pharmacopoeia, 28^th edition, The Pharmaceutical press, LONDON , ENGLAND; 1982 .
   
2. James E. Knoben & Philip O. Anderson, Handbood of clinical drug Data, 5^th edition,HAMILTON, ILLINOIS; 1983.
   
   
3. Ronald H. Girdwood, Clinical Pharmacology; 25^th edition;1984.
   
4. Stan Reets and Jonathan C. Seymour, Clinical Pharmacology, Gold standard Multi Media Incorporation, Version 1.0 ; 1994 .
   

• A study of a clinical case that relates certain muscle problems to Propoxyphene .

Let us recall the drug interaction of Propoxyphene which was mentioned at page 4, We find that there is an interaction between Propoxyphene and Muscle relaxants, To clear the effect of Propoxyphene on muscles I've presented a clinical case emphasizing that effect. The full text is shown in the last pages of this Report.

Problem list

1. Fatigue.
2. Maylgia (Muscle pain) . problems started Six month before Hospitalization

Post Medical History

1. Low back pain ( Chronic ).
2. Depression.

So for the last three years she had been takingAmitriptyline (75 mg) plus 600 mg of Darvon - N ( Propoxyphene Napsylate) in divided doses.

Physical examination

1. Normal Cranial nerves and neck muscle strength .
2. A four-fifth weakness in the proximal muscle of the upper and lower extremities .
3. Normal sensation .
4. Active and symmetrical reflexes .

Laboratory tests

1. Serum Creatine Kinase was 10600 Unit ( normal is 250 units ).
2. Three fold increase in Aspartate aminotransferase.
3. Three fold increase in Aldolase .
4. Other blood values were normal .
5. Electrolyte levels were normal .
6. Muscular biopsy showed no defect enzymatically nor fiber damage .

After 4 days of Hospitalization and Monitoring

1. CK levels returned to normal .
2. improvement in muscle strength .

She was discharged from hospital and two weeks later she

Redeveloped the symptoms with a CK level of 1500 unit .

IT was found that she was not so faithful about her medication , After questioning it turned out that she had largely exceeded her prescribed dose of Propoxyphene that it bounced of a level of 2600 mg daily which is equal to 20 Tablets of Darvon - N . And due to the discontinuation of Propoxyphene consumption in the hospitalization period, Her symptoms disappeared .

So the patient began Propoxyphene detoxification; and use of this drug was discontinued; symptoms shortly disappeared and levels of CK returned to Normal .

CASE COMMENTS

Side effects of Propoxyphene do not include Muscular effects; In fact this is the first case of such effect on the muscles . This effect on the Muscles is probably Potentiated by Amitriptiline which caused an increase in plasma levels of Propoxyphene. Still; Mechanism of muscle damage done by Propoxyphene is not known . Yet this drug must be included with drugs that cause muscular toxicity .

<< Dalakas- MC, Subacute painful Myopathy from Chronic Propoxyphene, Journal of Pharmaceutical Sciences (JAMA); 1986; vol. 255 (APR 4); page 1709 >>

• Effect of plasma exchange on treatment of Propoxyphene poisoning

Referring to what I've mentioned previously about effect of dialysis on intoxication of Propoxyphene, Propoxyphene is a highly distributive drug that widely distributes to the tissue especially the CNS , however; some effects of Propoxyphene are due to the Free plasma concentration of Propoxyphene, Mainly; Cardiac effects like Cardiac arrhythmia, And degree of Concies-nessis also related to the Free plasma concentration .

So Dialysis or Plasma exchange has it's importance . it does not have the same importance of Naloxone {Naloxone can neutralize the effect of respiratory depression but has no effect on the Arrhythmia's} , still it can be life saving as we shall see in the following mini-cases.

I must note that all of the patients who went through the PE (except for patient one) were given Phytomenadione . and that is to normalize the Prothrombin that was lost during the exchange.

Propoxyphene has a free drug level of 1%, While The rest distributes into tissue , And this Free concentration of Propoxyphene is responsible for the Conciseness and the Cardiac effects seen, It has been proved that sudden death one hour after ingestion of amounts as small as 10-30 mg/kg of Propoxyphene can happen. In our cases the amount was way beyond that concentration, Giving us a clue on the importance of Dialysis on Reducing toxicity . But one might ask; Why did patient one Die although he took less amount of drug than patient two for example ?. Well the answer to that is that patient one was hospitalized and undergone Dialysis 6 hours after Intoxication with the drug, In other words; Dialysis came a bit too late to be efficient. As a result patient one developed Severe Dysrhythmia and eventually Passed away . Patient two got the Plasma Exchange at an early stage of the intoxication , at a stage in which he only developed a first degree AV - heart block; and after Exchange this block ended and his life was saved. The rest of the patients did not even suffer any Cardiac complications in spite taking large amounts of the drug.

We must also note the effect of Dialysis on the level of Conciseness further proving the relation between free plasma concentration of the drug and degree of awakeness, We saw that patients who had dialysis recovered Conciseness. But the Coma reoccurred later due to the Slow Rebound effect of Propoxyphene from tissue. Case 6 is the only one in which there was mixed medications involved, But; Propoxyphene was mostly the cause of Coma .

Finally I must conclude this discussion of the Cases to say that Plasma Exchange is indeed effective in The detoxification of over dose of Propoxyphene provided that it is given as Quickly as possible ; otherwise it will not be effective and Sudden Cardiac dysrhythmias will follow, and eventually death .

<< B.Thamdrup,O.V. stergaard & E.Clausen, International Journal Of Clinical Pharmacology, Therapy, and Toxicology, Vol. 24, No. 7; 1986 Pages 379-380 >>