A new CDC guideline for prescribing opioids for pain recently became available. Nonopioid drugs for pain were reviewed in a previous issue.

View the Comparison Table: Some Oral/Transdermal Opioid Analgesics

Use of nonopioid drugs for pain was reviewed in a previous issue. For many types of moderate to severe acute pain, acetaminophen and/or an NSAID may be as effective as an opioid. Immediate-release formulations of full opioid agonists should generally be used for acute pain that is severe enough to require treatment with an opioid. Use of extended-release or long-acting opioid formulations initially and treatment durations >1 week have been associated with an increased risk of unintended long-term use.

View the Comparison Table: Some Oral/Topical Opioid Analgesics

A patient-controlled fentanyl iontophoretic transdermal system (Ionsys – The Medicines Company) is now available for short-term management of acute postoperative pain in adults requiring opioid analgesia in the hospital. Before using Ionsys, patients must be titrated to a comfortable level of analgesia with another opioid formulation.

Pain can be acute or chronic. The two major types of chronic pain are nociceptive pain and neuropathic pain. Nociceptive pain can be treated with nonopioid analgesics or opioids. Neuropathic pain is less responsive to opioids and is often treated with adjuvant drugs such as antidepressants and antiepileptics. Combining different types of analgesics may provide an additive analgesic effect without increasing adverse effects.

The FDA has approved a nasal spray formulation of fentanyl (Lazanda – Archimedes) for management of breakthrough pain in adult cancer patients who are already receiving and are tolerant to opioid therapy. Fentanyl is already available in the US for intravenous, intrathecal, epidural, transdermal and oral transmucosal use.

The FDA has approved the marketing of fentanyl sublingual tablets (Abstral – ProStrakan) for treatment of breakthrough pain in adult cancer patients who are already receiving and are tolerant to opioid therapy. It is the fourth transmucosal formulation of fentanyl to become available in the US for this indication.1-3

The manufacturer recommends an initial dose of 100 mcg, a maximum of 2 doses per breakthrough pain episode, and use for no more than 4 breakthrough pain episodes per day. As with all formulations of fentanyl, strong inhibitors of CYP3A4 such as clarithromycin (Biaxin, and others) or itraconazole (Sporanox, and others) can increase serum concentrations of the drug to levels that can cause respiratory depression even in opioid- tolerant patients. A single dose of any formulation of transmucosal fentanyl could be fatal for a child.

1. Fentanyl buccal tablet (Fentora) for breakthrough pain. Med Lett Drugs Ther 2007; 49:78.

2. Drugs for pain. Treat Guidel Med Lett 2010; 8:25.

3. Fentanyl buccal soluble film (Onsolis) for breakthrough cancer pain. Med Lett Drugs Ther 2010; 52:30.

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The FDA has approved the partial opioid agonist buprenorphine in a transdermal formulation (Butrans – Purdue) for treatment of moderate to severe chronic pain. Buprenorphine has been available in the US for years in parenteral formulations for pain and in sublingual tablets for opioid dependence.1 Transdermal buprenorphine has been available in Europe for several years.2

Fentanyl buccal soluble film (Onsolis – Meda) has been approved by the FDA for treatment of breakthrough pain in adult cancer patients who are already taking and are tolerant to around-the-clock opioid therapy. It is designated as a Schedule II controlled substance Two other oral transmucosal formulations of fentanyl are already available for this indication.

Pain can be acute or chronic. Chronic pain has been broadly classified into two types: nociceptive and neuropathic. Nociceptive pain can be treated with nonopioid analgesics or opioids. Neuropathic pain is less responsive to opioids; adjuvant medicines such as antidepressants and anticonvulsants are often used to treat neuropathic pain. Combining different types of analgesics may provide an additive analgesic effect without increasing adverse effects.

Transdermal fentanyl (Duragesic, and others) offers a convenient delivery system for patients with chronic pain1 but it has some drawbacks. One is that exposing the patch to heat, either from an external source, increased exertion or possibly high fever, could increase release of the drug, which might lead to an overdose and fatal respiratory depression.2 A recent article in the NY Times about this problem may have aroused the concerns of some patients using the patches.3

First approved for marketing by the FDA in 19914, transdermal fentanyl provides continuous delivery of the drug for about 3 days. After application of the patch, a depot of fentanyl forms in the upper layers of the skin. Serum concentrations of the drug increase gradually, reaching a peak (Cmax) in 24-72 hours. According to a pharmacokinetic model mentioned in the labeling, an increase in body temperature to 40°C (104°F) could increase fentanyl serum concentrations by 33%. Local application of heat near or on a fentanyl transdermal patch also increases systemic absorption; in one study, heating the patch during the first 4 hours after application increased maximum serum concentrations nearly three-fold.5 Unintentional increases in systemic fentanyl absorption caused by a heating pad, a warming blanket used during surgery and strenuous exertion have led to respiratory depression in 3 patients.6 No reports of clinical overdosage caused by fever have been published.

Serious adverse events may require removal of the patch and administration of an opioid antagonist such as naloxone (Narcan, and others). Monitoring for hypoventilation or cognitive impairment for at least 24 hours is recommended after removing the patch because fentanyl concentrations decrease slowly (50% decrease in about 17 hours) due to continued systemic absorption from the intracutaneous reservoir.

1. Drugs for pain. Treat Guidel Med Lett 2007; 5:23.
2. FDA Alert 7/15/2005; Update 12/21/2007. Information for healthcare professionals: Fentanyl transdermal system (marketed as Duragesic and generics). Available at www.fda.gov/cder/drug/InfoSheets/HCP/fentanyl_2007HCP.htm. Accessed July 27, 2009.
3. T Brown. Doctors and nurses, still learning. New York Times, April 29, 2009. Available at NYTimes.com. Accessed July 29, 2009.
4. Transdermal fentanyl. Med Lett Drugs Ther 1992; 34:97.
5. MA Ashburn et al. The pharmacokinetics of transdermal fentanyl delivered with and without controlled heat. J Pain 2003; 4:291.
6. KA Carter. Heat-associated increase in transdermal fentanyl absorption. Am J Health Syst Pharm 2003; 60:191.

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The FDA has approved a transmucosal tablet formulation of fentanyl citrate (Fentora - Cephalon) for management of breakthrough pain in opioid-tolerant patients with cancer. An oral transmucosal fentanyl lozenge on a stick (Actiq, and others) is also available for this indication, and is widely used off-label for chronic, non-cancer pain as well.

Pain can be acute or chronic. Chronic pain has been broadly classified into two types: nociceptive and neuropathic. Nociceptive pain is generally treated with nonopioid analgesics and opioids. Antidepressants and anticonvulsants have been used to treat neuropathic pain. Combining two different types of analgesics may nprovide an additive analgesic effect without increasing adverse effects.

The Medical Letter review of Palladone (hydromorphone HCl) extended-release capsules (March 14, 2005) warned that a lethal dose could be released if the new formulation was taken with alcohol. Because of that risk, the FDA asked the manufacturer (Purdue) to withdraw the drug from the market (FDA News. July 13, 2005; FDC Reports – “The Pink Sheet” July 18, 2005; 67:3).

Serious adverse interactions between drugs continue to be reported. Many of these are due to inhibition or induction of cytochrome P450 (CYP) enzymes, particularly CYP3A4. CYP3A is thought to be involved in the metabolism of more than 50 percent of currently prescribed drugs.2 CYP3A4, which is more abundantly expressed than CYP3A5, accounts for most CYP3A activity in vivo.

A once-daily extended-release (ER) oral formulation of the opioid analgesic hydromorphone hydrochloride (Palladone - Purdue Pharma) has been approved by the FDA for treatment of opioid-tolerant patients with persistent moderate to severe pain. Hydromorphone HCl, a semisynthetic congener of morphine and active metabolite of hydrocodone that has been used since the 1920s, is also available in immediate-release oral, injectable and suppository forms (Dilaudid, and others).

Three types of analgesic drugs are available: non-opioids, including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; opioids; and adjuvant drugs that are not usually thought of as analgesics, such as antidepressants, which can act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain. Combining two different types of analgesics may provide an additive analgesic effect without necessarily increasing adverse effects.

Changes caused by one drug in the absorption, distribution, metabolism or excretion of another may lead to a pharmacokinetic adverse drug interaction (DN Juurlink et al, JAMA 2003; 289:1652). Additive drug interactions, such as vasodilation caused by both sildenafil (Viagra) and nitrates, can also have adverse effects.

Acute toxic reactions to drugs of abuse continue to be important problems. Some patients may have mixed intoxications with complex combinations of signs and symptoms.

Three types of analgesic drugs are available: first, non-opioids, including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; second, opioids; and third, drugs not usually thought of as analgesics, which act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain. Non-opioids can be given concurrently with opioids for an additive analgesic effect.

Reports of adverse interactions between drugs continue to accumulate. Recently, the FDA has expanded the recommendations on drug interactions found in the package inserts of new drugs.

Three types of analgesic drugs are available: first, non-opioids, including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; second, opioids; and third, some drugs not usually thought of as analgesics, which act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain.

Sibutramine hydrochlorid monohydreate (Meridia - Knoll), which is structurally related to amphetamine, has been approved by the FDA for treatment of obesity. It is classified by the Drug Enforcement Agency (DEA) as a schedule IV controlled substance.

Acute toxic reactions to drugs of abuse continue to be important problems. Since the last Medical Letter article on this subject (volume 32, page 92, 1990), new reactions and new approaches to treating them have been reported.

Nalmefene (Revex - Ohmeda), an i methylene analog of naltrexone (Trexan), is a long-acting opioid antagonist that has been approved by the US Food and Drug Administration for reversal of postoperative opioid drug effects, including respiratory depression, sedation and hypotension and for management of known or suspected opioid overdose in the emergency department. The only other opioid antagonists available in the USA are naloxone (Narcan), which is also injectable but has a short duration of action, and naltrexone, which has a long duration of action but is marketed only for oral use.

Three types of analgesic drugs are available in the USA: first, aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; second, opioids; and third, drugs not usually thought of as analgesics, which act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain. (American Pain Society, Principles of analgesic Use, 3rd ed, Skokie, illinois: American pain society, 1992).

Fentanyl, a synthetic opioid previously available for parenteral use in anesthesia (Sublimaze), has now been marketed in a controlled-release transdermal formulation (Duragesic - Janssen) for use in patients with chronic pain severe enough to require opioid analgesia. It is not recommended for treatment of postoperative pain because of the drug's slow onset and prolonged duration of action.

Percutaneous transluminal coronary angioplasty (PTCA), in which a balloon catheter distends the vessel at the site of obstruction (Medical Letter, 25:97, 1983), is now an established therapeutic option for treatment of patients with coronary artery disease, especially those with single-vessel disease. Major problems related to PTCA include acute occlusion during the procedure (usually caused by dissection), restenosis at the site of angioplasty, and inability to treat complete occlusions and long or ostial lesions. Some cardiologists have tried using lasers during PTCA to deal with these problems.