VA Class:CV900
Papaverine hydrochloride is a vasodilating agent.
Papaverine hydrochloride is used principally for the relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated by arrhythmias.180 The drug also has been used to increase collateral circulation in the treatment of acute vascular occlusion. For this condition it has been used in conjunction with anticoagulants and has usually been administered IV, although it has also been administered intra-arterially.
Papaverine hydrochloride has been used in the treatment of angina pectoris, but it has not shown impressive results at the usual therapeutic dosage and papaverine is not recommended as a substitute for nitroglycerin in anginal attacks. Papaverine also has been used in the treatment of a wide variety of other cardiovascular or vascular conditions including vascular encephalopathy associated with hypertensive disease, certain cerebral angiospastic states, and chronic peripheral vascular diseases such as Raynaud's syndrome and Buerger's disease; however, its use in these conditions has been superseded by more effective agents.
Self-injection of papaverine hydrochloride (2.5-37.5 mg, but usually titrated up to 30 mg), combined with small doses of phentolamine mesylate (0.08-1.25 mg, but usually 0.5-1 mg) into a corpus cavernosum of the penis has been effective for the treatment of erectile dysfunction† (ED, impotence);178 patients with neurogenic impotence generally respond to lower dosages than those with vasculogenic impotence.103, 105, 106, 107, 108, 110, 112, 113, 114, 115, 116, 118, 119, 120, 121, 126, 128, 132, 137, 142 Injection into a single cavernosum can increase tumescence (in both cavernosa because of cross circulation) and produce erection probably secondary to drug-induced increased arterial inflow and sinusoidal relaxation and decreased venous outflow (from increased venous resistance).105, 106, 108, 110, 116, 117, 121, 129, 132 The goal of such therapy is to provide an erection of adequate rigidity and duration to be sexually functional while avoiding prolonged erection or priapism.142, 143, 144, 145, 146, 147 While one manufacturer has stated that parenteral papaverine hydrochloride is not indicated for the treatment of impotence via intracorporeal injection,133, 134, 135 intracavernosal papaverine (alone or combined with phentolamine and/or alprostadil) is one of the most effective and well-studied agents for this condition and has been in widespread clinical use.103, 105, 106, 107, 108, 110, 112, 113, 114, 115, 116, 118, 119, 120, 121, 126, 128, 130, 132, 137, 138, 139, 140, 141, 142 The combination has been effective in patients with neurogenic103, 105, 106, 108, 110, 112, 113, 115, 116, 118, 119, 120, 128, 129, 132 and/or limited vasculogenic impotence103, 105, 106, 108, 110, 112, 113, 115, 116, 120, 121, 128, 129, 132 or with psychogenic impotence,105, 106, 108, 120, 128, 129, 132 but efficacy in those with a vasculogenic component of their impotence may be variable depending on the extent and type of vascular dysfunction.103, 108, 110, 115, 120, 128, 129 Erection, which can be potentiated by sexual arousal, usually occurs within 10 minutes after injection of the drugs and may persist for one to several hours;105, 106, 108, 112, 113, 114, 116, 118, 119, 129, 132 tolerance to the beneficial vascular effects of the drugs may occur during long-term use and may require an increase in dosage.105, 114, 129 Occasionally, priapism may occur.103, 105, 106, 107, 108, 110, 113, 115, 116, 127, 129, 132, 133, 138 (See Cautions: Adverse Effects.) Intracavernous papaverine hydrochloride occasionally has been used alone for the treatment of impotence.105, 112, 121, 122, 123, 124, 125, 127, 128, 129
Because of their convenience (e.g., ease of administration, patient and partner acceptance, and effectiveness in a broad range of patients, most experts (e.g., the American Urological Association [AUA]) currently recommend that selective phosphodiesterase (PDE) type 5 inhibitor therapy (sildenafil, tadalafil, vardenafil) be offered as first-line treatment of erectile dysfunction unless contraindicated.178 Intracavernosal therapy with papaverine and/or other drugs generally is reserved for patients who do not respond to psychotherapy/behavioral therapy, vacuum constriction devices, and/or selective PDE type 5 inhibitors and in whom attempts at identifying and modifying any drug-related (e.g., certain antihypertensive agents) or other potential reversible medical cause of erectile dysfunction have proved inadequate.110, 130 Intracavernosal therapy or vacuum constriction devices generally are considered or attempted before resorting to more invasive (e.g., surgical) therapies.130, 142, 178 Ultimately, the choice of therapy for erectile dysfunction should be individualized taking into account differences in response, tolerability and safety, administration considerations, cost and patient reimbursement factors, experience and judgment of the clinician, and individual patient and partner preference, expectations, and satisfaction.170, 171, 172, 173, 174, 175, 176, 177, 178
Intracavernosal vasoactive therapy (e.g., papaverine, papaverine and phentolamine, alprostadil) is the most effective treatment for erectile dysfunction;179 however, it is invasive and associated with the highest risk of priapism.178 Clinician preference and experience often guide the initial treatment choice when intracavernosal therapy is indicated.178
Although additional study of the long-term safety and efficacy of intracavernosal injection of vasoactive drugs for the treatment of impotence is necessary and ongoing, particularly regarding the relative complications (e.g., penile scarring, penile fibrosis) and safety of each approach, some clinicians currently favor alprostadil, alone or combined with other agents, when intracavernosal treatment of impotence is indicated because of possible improved efficacy and decreased adverse effects (e.g., priapism, fibrotic changes) compared with papaverine therapy.130, 149, 150, 151, 152, 153, 154 However, all currently popular forms of therapy for impotence, including intracavernosal vasoactive therapy, have been associated with high dropout rates, often early in treatment (e.g., secondary to adverse effects, compromised sexual spontaneity, loss of motivation of partner, spontaneous return of function).154, 156, 157, 158, 159, 160, 161, 162 The motivations and expectations of the patient and his partner, and the education, as well as inclusion in the treatment plan, of both partners are critical in facilitating efficacy and compliance.132, 137, 155, 163, 166, 167 Provision of continued education and adequate follow-up support, including determination of reasons for unacceptable response and for discontinuance of therapy if this occurs as well as discussion of treatment options, also are important,130, 159, 168 although additional study is needed to identify optimal interventions that might improve compliance and decrease dropout.130, 156, 157, 158, 159, 160, 161, 169 Patients should be instructed to visit their clinician regularly (e.g., at 3-month intervals) for assessment of therapeutic benefit, including the need for possible dosage adjustment, and of potential adverse effects of their therapy.143, 147, 159, 167
Occasionally, it may be possible to discontinue vasoactive therapy because normal erectile function returns.138, 148, 154, 155, 157, 159 In such cases, normal erectile functioning may result from decreased anxiety, improved self-confidence (e.g., in those with psychogenic impotence), or improved penile circulation in those with vasculogenic impotence.110, 159, 164
Vasoactive therapy for impotence should not be used in patients who might have conditions predisposing to priapism (e.g., sickle cell anemia or trait, multiple myeloma, leukemia), in those with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie's disease), or in men for whom sexual activity is inadvisable or contraindicated.110, 143, 152, 154, 164, 165, 167 In addition, vasoactive therapy should be discontinued in any patient who develops penile angulation, cavernosal fibrosis, or Peyronie's disease during therapy with the drug.143, 167 One manufacturer also states that patients with penile implants should not be treated with vasoactive therapy for impotence.143
Because of the risk of priapism and other potential complications (e.g., adverse morphologic penile effects such as fibrosis) associated with intracavernosal vasoactive therapy, such therapy is not recommended for simply enhancing erections in men who are not impotent.154
Although papaverine has been used in the treatment of GI spasms, dysmenorrhea, biliary or ureteral colic, bronchial asthma, cardiac arrhythmias, and other pathologic conditions, there is not sufficient evidence to establish the therapeutic value of papaverine in these or any other conditions and it has been generally discarded by most clinicians.
Papaverine hydrochloride may be administered orally, or by IM or slow IV injection.180, 181 The IV route is recommended when an immediate effect is desired, but the drug must be injected slowly over a 1- to 2-minute period to avoid serious adverse effects.181 (See Cautions: Precautions and Contraindications.)
Papaverine hydrochloride, alone or combined with phentolamine mesylate, also has been administered by intracavernous† injection for the treatment of erectile dysfunction.103, 105, 106, 107, 108, 110, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127 (See Uses: Erectile Dysfunction.) Patients receiving the drug via intracavernosal injection should be advised of the potential for prolonged erections (priapism) and informed of steps to take in the event that this potentially serious adverse effect occurs.178, 179 (See Adverse Effects: Adverse Intracavernosal Effects, in Cautions.)
The usual adult oral dosage of papaverine hydrochloride is 150 mg (as extended-release capsules) every 8-12 hours.180 Alternatively, 300 mg (as extended-release capsules) may be given every 12 hours.180 A dosage of 75-300 mg (as conventional tablets [no longer commercially available in the US]) 3-5 times daily also has been used.
The usual adult parenteral dose of papaverine hydrochloride is 30 mg; however, a dosage of 30-120 mg may be repeated every 3 hours as necessary. In the treatment of cardiac extrasystoles, 2 doses may be administered 10 minutes apart.181 Children may receive 6 mg/kg daily, divided into 4 IM or IV doses.
Although the toxicity of papaverine hydrochloride is low following oral administration, adverse effects attributable to the effects of drug on the autonomic nervous system may include general discomfort, flushing of the face, sweating, dryness of the mouth or throat, pruritus, hypotension or an increase in blood pressure, and increased depth of respirations. Depression, dizziness or vertigo, headache, drowsiness, sedation, lassitude, rash, hypertension,181 increases in heart rate, malaise, general discomfort,181 or lethargy also may occur. Adverse GI effects including constipation, nausea, diarrhea, abdominal distress, and anorexia have been reported. Hepatitis (probably related to an immunologic mechanism) also has been reported, and, rarely, has progressed to cirrhosis. Hepatic hypersensitivity with GI symptoms, jaundice, eosinophilia, and altered hepatic function test results has also been reported. Thrombosis at the site of IV administration also has occurred.
Adverse Intracavernosal Effects
Intracavernous injection† of papaverine alone or combined with phentolamine for the treatment of impotence occasionally has caused priapism.103, 105, 106, 107, 108, 110, 113, 115, 116, 120, 122, 125, 127, 129, 130, 131, 132, 137, 178 Priapism is a medical emergency that could result in penile tissue damage and permanent loss of potency if not treated immediately, and therefore, patients should be advised to report promptly to their physician or, if unavailable, to seek alternative immediate medical attention if an erection that persists longer than 4 hours or that is extremely painful occurs. Management of priapism should be according to established medical practice, and has included aspiration of cavernosal blood105, 110, 113, 115, 116, 120, 127, 129 and/or intracavernous injection of an α-adrenergic agonist (e.g., metaraminol, phenylephrine) or dopamine.103, 105, 106, 107, 108, 109, 110, 111, 113, 115, 120, 127, 129, 137, 179 Rarely, more radical therapy for priapism (e.g., cavernospongiosus or Winter's shunt) may be necessary,104, 105, 106, 110, 129, 179 such as in patients with persistent priapism (e.g., for longer than 24 hours).104, 110
Other complications of intracavernous injection of papaverine, alone or combined with phentolamine, have included transient pain,105, 108, 110, 129 including referred pain to the glans,108, 110, 129 burning,103 and paresthesia.105, 110, 129 Penile ecchymosis has occurred in many patients,105, 110, 113, 129 and superficial hematoma103, 110, 127 and bruising of the penis106, 108 also have occurred. Fibrotic changes (e.g., induration, lumpy areas of the penis but not necessarily at the injection site), including bilateral fibrosis of the corpora cavernosa, also have been reported.105, 110, 114, 129, 137 Embolus in the glans has been reported rarely,105, 108, 129 and the development of priapism, deep-vein thrombosis, and fatal pulmonary embolus occurred in one patient.105, 129 Adverse systemic effects of the drugs (e.g., facial flushing,110 dizziness,103, 110, 120, 127 decreased systemic blood pressure,105, 108, 110, 129 metallic taste)103 also have occurred.103, 105, 108, 110
The risk of priapism, although reportedly uncommon, can be reduced by careful patient instruction and dosage titration.132, 137, 142 Alternatively, switching to another therapy (e.g., alprostadil) may provide better patient tolerance.132, 137, 142 Some clinicians also have used alprostadil in combination with papaverine and phentolamine in an attempt to potentiate their therapeutic activity, reduce the dose of each drug required, and decrease the risk of local pain, penile corporal fibrosis, fibrotic nodules, hypotension, and priapism associated with higher dosages.130, 138, 139, 140, 141, 142, 178 However, additional study is needed to elucidate the long-term safety and benefits of such combined therapy.130, 140
Precautions and Contraindications
Papaverine hydrochloride should be administered with caution to patients with glaucoma. Papaverine hydrochloride injection should be used by or under the immediate supervision of a physician. IV administration of the drug should be performed cautiously since arrhythmias and fatal apnea may result from rapid injection. If any signs or symptoms of hepatic hypersensitivity occur in patients receiving papaverine, the drug should be discontinued.180, 181
The possibility that intracavernosal papaverine therapy for impotence could result in persistent priapism requiring medical and/or surgical intervention should be considered.103, 105, 106, 107, 108, 110, 113, 115, 116, 120, 122, 125, 127, 129, 130, 131, 132, 133, 134, 135, 137 (See Cautions: Adverse Intracavernosal Effects.) Patients should be advised to contact their clinician if they develop a persistent (e.g., longer than 4 hours) erection during such therapy.132, 142 While one manufacturer has stated that papaverine hydrochloride injection is not indicated for the treatment of impotence via intracorporeal injection,133, 134, 135 the drug has been employed effectively via intracavernosal injection for the treatment of this condition.103, 105, 106, 107, 108, 110, 112, 113, 114, 115, 116, 118, 119, 120, 121, 126, 128, 130, 132, 137, 142 (See Uses.) The possibility that intracavernosal therapy may be problematic in patients receiving anticoagulants or who cannot tolerate transient hypotension and, because of the self-injection techniques involved, in those with poor manual dexterity, poor vision, or severe psychiatric disease also should be considered.130 For additional precautions and contraindications associated with vasoactive therapy in impotence, see Uses.
Papaverine hydrochloride is contraindicated in the presence of complete atrioventricular heart block and must be administered with extreme caution when conduction is depressed since the drug may produce transient ectopic rhythms of ventricular origin, either premature beats or paroxysmal tachycardia.
Safety and efficacy of papaverine hydrochloride in children have not been established. Children have received papaverine hydrochloride dosages of 6 mg/kg daily, divided into 4 IM or IV doses.
Pregnancy, Fertility, and Lactation
No teratogenic effects were reported in rats receiving subcutaneous administration of papaverine hydrochloride as a single drug. It is not known whether papaverine can cause fetal harm when administered to pregnant women; it is also not known if the drug can affect reproduction capacity. Papaverine should be used during pregnancy only when clearly needed.
It is not known whether papaverine distributes into human milk. Because many drugs are distributed into milk, papaverine hydrochloride should be used with caution in nursing women.
The effects of papaverine hydrochloride may be slightly potentiated by CNS depressants and a synergism may result from combination with morphine.
Papaverine may interfere with the therapeutic effects of levodopa in patients with Parkinson's disease when the drugs are administered concomitantly. The mechanism of this interaction is not known, but it has been suggested that papaverine may block dopamine receptors. Use of papaverine in patients with Parkinson's disease should probably be avoided, particularly if the patients are receiving levodopa.
The oral LD50 of papaverine hydrochloride in rats is 360 mg/kg.
In general, overdosage of papaverine may be associated with manifestations resulting from vasomotor instability, including nausea, vomiting, weakness, CNS depression, nystagmus, diplopia, diaphoresis, flushing, dizziness, and sinus tachycardia. With large overdoses, papaverine is a potent inhibitor of cellular respiration and a weak calcium-channel blocking agent. Following a 15-g oral dose of papaverine hydrochloride, metabolic acidosis with hyperventilation, hyperglycemia, and hypokalemia has been reported. No information is available on the toxic serum concentrations of papaverine.
Following IV administration of papaverine overdoses in animals, seizures, tachyarrhythmias, and ventricular fibrillation have been reported.
One manufacturer states that in case of papaverine overdosage a poison center should be contacted to receive the most current information on the treatment of such overdosage. This manufacturer also states that the possibility of multiple drug overdosage, drug interactions, and unusual pharmacokinetics of concomitantly used drugs also should be considered. In case of papaverine overdosage, the patient's airway should be protected and ventilation and perfusion supported. Vital signs, blood gases, and blood chemistry values should be carefully monitored. If seizures occur, they may be treated with diazepam, phenytoin, or phenobarbital. In case of refractory seizures, thiopental (no longer commercially available in the US) or halothane may be used to produce general anesthesia and a neuromuscular blocking agent may be necessary to produce paralysis. Administration of IV fluids, elevating the patient's legs, and/or a vasopressor (e.g., dopamine, norepinephrine) may be used to treat hypotension. Calcium gluconate may be useful for the treatment of papaverine-induced adverse cardiac effects; plasma calcium concentrations and ECG should be monitored. It is not known if papaverine is removed by forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion.
Because of the abuse potential of CNS depressant drugs, including papaverine, dependence to the drug has been reported.
The principal therapeutic action of papaverine is its spasmolytic effect on smooth muscles. The spasmolytic effect of papaverine is most pronounced on blood vessels including the coronary, cerebral, pulmonary, and peripheral arteries; it also relaxes smooth muscles of the bronchi, GI tract, ureters, and biliary system. Animal studies indicate that the coronary dilator action of papaverine hydrochloride may be potentiated by previous reserpinization. Papaverine relaxes cardiac muscle by directly depressing the excitability of the myocardium, prolonging the refractory period, and depressing conduction.
The spasmolytic effect of papaverine is direct and unrelated to muscle innervation. In the presence of vascular occlusion, the drug may act by overcoming reflex vasoconstriction in collateral vessels. Animal studies indicate that papaverine may have a dual mechanism of spasmolytic action involving both the inhibition of oxidative phosphorylation and interference with calcium during muscle contraction.
Direct vasodilating action of papaverine hydrochloride may explain the benefit reported in cerebrovascular encephalopathy.180
Papaverine has minimal CNS actions, although large doses may have a depressant effect in some patients. The drug also exhibits weak calcium-channel blocking activity at high doses. Papaverine has little, if any, analgesic action.
Papaverine hydrochloride is readily absorbed from the GI tract and has a fairly rapid onset of action. The drug is distributed throughout the body, with highest concentrations appearing in fat deposits and the liver.181 Estimates of the biological half-life vary, but reasonably constant plasma concentrations can be maintained with oral administration at 6-hour intervals. As much as 90% of the drug may be bound to plasma proteins. Very limited studies suggest that the administration of an extended-release oral dosage form may provide continuous release of papaverine hydrochloride over a 12-hour period.
Papaverine hydrochloride is rapidly metabolized by the liver and excreted in the urine, chiefly as glucuronide conjugates of phenolic metabolites.
Papaverine hydrochloride is a benzylisoquinoline alkaloid prepared synthetically or obtained from opium. Papaverine is chemically and pharmacologically distinct from morphine, and it does not evoke tolerance or addiction. Papaverine hydrochloride occurs as white crystals or as a white, crystalline powder that is odorless and has a slightly bitter taste. The drug is soluble in water and slightly soluble in alcohol. Papaverine hydrochloride injection is a clear, colorless to pale yellow solution.133
Papaverine hydrochloride preparations should be stored at a temperature less than 40°C, preferably between 15-30°C; freezing of the injection should be avoided. The extended-relase capsules should be protected from moisture.180 Papaverine hydrochloride injection should be protected from light and kept in its original carton until ready for use.181 Papaverine hydrochloride injection should not be added to lactated Ringer's injection because a precipitate would result.
Following reconstitution of phentolamine mesylate lyophilized powder with 2 mL of commercially available papaverine hydrochloride injection (containing 30 mg/mL) and further dilution in 8 mL of the papaverine injection to provide an admixture containing 30 mg of papaverine hydrochloride per mL and 0.5 mg of phentolamine mesylate per mL, the resultant admixture had a pH of 3.6 and was stable for at least 30 days when stored in the papaverine vial at 5 or 25°C.100 It should be noted, however, that the manufacturer of papaverine hydrochloride injection recommends that the injection not be refrigerated since solubility of the drug is reduced at cold temperatures, possibly resulting in precipitation or crystallization.101, 102 In addition, the possibility of microbial contamination of such admixtures during prolonged storage should be considered.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Bulk | Powder | |||
Oral | Capsules, extended-release | 150 mg* | Papaverine Hydrochloride Capsules ER | |
Para-Time® SR | ||||
Parenteral | Injection | 30 mg/mL* | Papaverine Hydrochloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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