General Information: Injectable papaverine has been studied via intra-arterial, intrathecal, intraluminal, perivascular, and intercavernous routes. In patients with severe vasospasm following aneurysmal subarachnoid hemorrhage, papaverine can be injected directly into cerebral arteries to prevent the development of delayed ischemic neurologic deficits. Papaverine can also be used in these patients to facilitate dilation of cerebral vessels prior to balloon angioplasty.1 Intra-arterial injection of papaverine has also been successful for the treatment of non-occlusive mesenteric ischemia.2 In patients undergoing diagnostic cardiac catheterization, intracoronary papaverine can be used to evaluate coronary flow reserve. Because of the potential for adverse cardiac effects, alternate agents such as adenosine may be more appropriate in these settings.3 Intrathecal injection of papaverine into the cerebrospinal fluid prior to aortic cross-clamping can prevent spinal cord neurologic injury in patients undergoing thoracoabdominal aortic surgery.4 Papaverine has also been administered by topical application, intraluminal injection, or perivascular injection in patients undergoing venous and arterial graft harvesting. Papaverine has been shown to improve blood flow through grafted arteries and veins by preventing vasospasm.56 Intercavernous injections of papaverine, either alone or combined with phentolamine and/or alprostadil, have been widely used for the treatment of erectile dysfunction.78 According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy.8 Second-line treatment options include intracavernous injection and intra-urethral therapy. Intracavernous injection therapy is the most effective nonsurgical treatment for ED, with predictable and sustained response. However, it is invasive and caries notable side-effects including priapism and penile fibrosis.8
Mechanism of Action: Papaverine is a benzylisoquinoline alkaloid of opium. It is structurally different from morphine and codeine, which are phenanthrene alkaloids. Papaverine acts by inhibiting phosphodiesterase in smooth muscle cells, which produces increased tissue levels of cyclic adenosine monophosphate and cyclic guanosine 3,5-monophosphate and subsequent relaxation of vascular smooth muscle.9 Calcium ion channels in cell membranes may also be blocked by papaverine, resulting in a reduction of release of calcium from the intracellular spaces.1 Papaverine has a spasmolytic effect on smooth muscle of the large blood vessels, particularly those of the coronary, cerebral, peripheral and pulmonary arteries. This spasmolytic effect is unrelated to muscle innervation, and the muscle cell is still responsive to drugs and other stimuli which cause contraction. Relaxation of smooth muscle is also produced in the bronchial musculature, and in the gastrointestinal, biliary, and urinary tracts. Papaverine also relaxes cardiac muscle by directly depressing conduction and excitability of the myocardium and prolonging the refractory period.
Pharmacokinetics: Papaverine is administered orally and parenterally. Papaverine is metabolized in the liver to inactive metabolites, which are excreted in the urine.
Special Populations: Hepatic Impairment: Data are lacking regarding the use of papaverine in hepatically impaired patients.
Indications: Papaverine is indicated in the treatment of arterial thromboembolism and is used off-label for the treatment of erectile dysfunction, cerebral and peripheral ischemia associated with arterial spasm, cardiac extrasystoles associated with myocardial ischemia, non-occlusive mesenteric ischemia, and vasospasm following aneurysmal subarachnoid hemorrhage. This article will primarily concentrate on papaverine's use in the treatment of erectile dysfunction.
For the off-label treatment of erectile dysfunction (ED):
Adult males: Papaverine is used alone, or in combination with phentolamine, or with phentolamine plus alprostadil (prostaglandin E1 or PGE1).10 Individual dosages are determined by a series of trial injections under physician supervision. The injections should be given no more than 3 times per week, with a minimum of 24 hours between doses.10 The maximum amount of papaverine is 60 mg per dose when given in combination therapy. Triple drug therapy with papaverine, phentolamine, and alprostadil is most effective, with response rates of up to 92%. Studied dose ranges are as follows:9
-Monotherapy: 20—80 mg papaverine per injection.
-2-drug regimen: 0.25—1.5 mg phentolamine + 7.5—45 mg papaverine per injection.
-3-drug regimen: 0.2—0.4 mg phentolamine + 8—16 mg papaverine + 10—20 mcg alprostadil per injection.
-Second line treatment options for ED include intracavernous injections; such therapy is the most effective nonsurgical treatment for ED, with predictable and sustained response. However, it is invasive and caries notable side effects, including priapism and penile fibrosis. Careful dose selection, proper patient education, and continued monitoring by a prescribing physician is warranted for successful non-oral treatment of ED. Follow-up visits for ED patients, regardless of therapy, are necessary to determine whether therapy continues to be effective and whether cardiovascular health has significantly changed.10
Contraindications and Precautions: Although the manufacturer indicates that injectable papaverine should be administered with caution to patients with glaucoma,11 review of the literature suggests that cautious use is not warranted for intracavernous use of the drug.12
Papaverine is contraindicated in the presence of complete atrioventricular block (AV block). When conduction is depressed, the drug may produce transient ectopic rhythms of ventricular origin, either premature beats or paroxysmal tachycardia.11
Patients with Parkinson's disease who are taking levodopa should avoid the use of papaverine. Loss of control of Parkinson's disease may result when papaverine is used in these patients. The mechanism of the interaction is unclear, but may be related to the blockage of dopamine receptors in the striatum by papaverine.
Papaverine may cause excessive drowsiness in some individuals. Instruct patients to use caution while driving or operating machinery.
Intracoronary papaverine may cause torsade de pointes in a small number of patients. Caution should be exercised when administering intracoronary papaverine to patients with preexisting QT prolongation.13
Papaverine is classified in FDA pregnancy risk category C. Following single subcutaneous doses of papaverine in rats, no teratogenic effects were reported. Safe use during pregnancy in humans has not been established. It is not known whether papaverine can affect reproduction capacity. According to the manufacturer, papaverine should only be given to a pregnant woman when clearly needed and when the potential benefits outweigh the potential hazards to the fetus.11 In addition, because papverine relaxes smooth muscle tone; use caution when considering administration to a woman in labor.
It is not known whether papaverine is excreted in human milk. According to the manufacturer, papaverine should be used with caution in women who are breast-feeding.11 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Clinical trials of extended-release papaverine capsules did not include enough geriatric patients to identify a difference in drug response as compared to younger patients. Subsequent clinical experience has not identified any differences. Nevertheless, due to an increased frequency of comorbidities and decreased hepatic and renal function, dosing in the elderly should start at the low end of the dosing range.
Although papaverine is used off-label for the treatment of erectile dysfunction, the manufacturer notes that papaverine is not indicated for the treatment of impotence by intracorporeal injection. The intracorporeal injection of papaverine hydrochloride has been reported to have resulted in persistent priapism requiring medical and surgical intervention.11 Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.
Pregnancy: Papaverine is classified in FDA pregnancy risk category C. Following single subcutaneous doses of papaverine in rats, no teratogenic effects were reported. Safe use during pregnancy in humans has not been established. It is not known whether papaverine can affect reproduction capacity. According to the manufacturer, papaverine should only be given to a pregnant woman when clearly needed and when the potential benefits outweigh the potential hazards to the fetus.11 In addition, because papverine relaxes smooth muscle tone; use caution when considering administration to a woman in labor.
Breast-Feeding: It is not known whether papaverine is excreted in human milk. According to the manufacturer, papaverine should be used with caution in women who are breast-feeding.11 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Interactions: Papaverine may block dopamine receptors in the striatum and result in loss of control of Parkinson's disease in patients who are taking levodopa. Patients with Parkinson's disease who are taking levodopa should avoid the use of papaverine.14
Papaverine is a benzylisoquinoline alkaloid of opium,15 and may have synergistic effects with opiate agonists such as morphine. Concurrent use of papaverine with potent CNS depressants such as ethanol, general anesthetics, or anxiolytics, sedatives, and hypnotics (including barbiturates and benzodiazepines) could lead to enhanced sedation.
Additive hypotensive effects can occur with the concomitant administration of diazoxide with peripheral vasodilators including papaverine. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.16
Adverse Reactions/Side Effects: Papaverine is reported to infrequently cause hepatitis that can rarely progress to cirrhosis.11 Hepatitis with elevated hepatic enzymes and abdominal pain has been documented with oral papaverine and elevated hepatic enzymes have also been noted following intracavernosal injection. Hepatotoxicity secondary to papaverine is believed to be immune mediated. There have also been case reports of chronic papaverine hepatotoxicity manifested by chronic active hepatitis and cirrhosis following long term treatment with oral papaverine. Histologic lesions suggest an immune mechanism is also responsible for chronic toxicity.
Other adverse effects associated with the use of papaverine include abdominal discomfort, anorexia, constipation, diarrhea, diaphoresis, intense flushing of the face, headache, hypertension, malaise, nausea, sinus tachycardia, increase in depth of respiration, excessive drowsiness (sedation), rash (unspecified), and vertigo. The exact incidence of these effects is unknown.11
Orthostatic hypotension has been reported following intracavernosal injection of papaverine.17 Prolonged erection, or priapism is a serious complication of intracavernosal injection of papaverine. Beginning with a low initial trial dose can minimize the potential for this adverse effect and titrating to the lowest dose that produces a satisfactory response.18 Patients should be instructed to seek medical attention for erection lasting longer than 4 hours. Intracavernosal injection of papaverine may result in an injection site reaction. Local site reactions may include transient penile pain, ecchymosis, and penile fibrosis at the injection site. Fibrosis may be avoided by ensuring proper injection technique and limiting the frequency of injections.18
One case of papaverine-induced seizures has been reported in the literature. Generalized convulsions developed following 300 mg of intra-arterial papaverine (internal carotid) in a patient being treated for symptomatic vasospasm after subarachnoid hemorrhage. This occurred despite therapeutic phenytoin levels. Repeat intra-arterial papaverine again produced seizures.19
Severe, reversible thrombocytopenia related to intra-arterial papaverine has been described in one case report. On two separate occasions, the same patient developed severe thrombocytopenia following injection of papaverine into the right internal carotid artery. Laboratory data supported the diagnosis of immune-mediated papaverine-induced thrombocytopenia.20
Increased intracranial pressure, hypertension, and sinus tachycardia have been noted during intra-arterial infusions of papaverine for vasospasm secondary to aneurysmal subarachnoid hemorrhage. These effects can be minimized by careful titration of papaverine in conjunction with hemodynamic monitoring.21
QT prolongation, ventricular arrhythmias, and torsade de pointes are rare complications of intracoronary administration of papaverine.22 In one series, five of 391 patients (1.3%) experienced polymorphous ventricular tachycardia. Only one patient required electrical cardioversion for resolution of the arrhythmia.13
This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.
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