The FDA has approved RiVive (Harm Reduction Therapeutics), a 3-mg naloxone nasal spray, as an over-the-counter (OTC) product for emergency treatment of opioid overdose. Two 4-mg naloxone nasal spray formulations, Narcan and one of its generics, were approved for OTC sale in 2023.

The FDA has approved an intranasal formulation of the opioid antagonist nalmefene (Opvee – Indivior) for emergency treatment of known or suspected opioid overdose in persons ≥12 years old. Nalmefene, which is available by prescription, is the second opioid antagonist to become available as a nasal spray for this indication; the first was naloxone, which is now available for sale over the counter (Narcan, and generic). Other nasal spray formulations of naloxone and injectable formulations of nalmefene and naloxone are available by prescription (see Table 2).

Since the publication of our articles entitled Drugs for Opioid Use Disorder and In Brief: Over-the-Counter Narcan Nasal Spray earlier this year, Narcan (Emergent), a nasal spray that delivers 4 mg of the opioid antagonist naloxone, has become available for sale over the counter (OTC). According to the manufacturer, the retail price for a box containing 2 doses is $44.99. Some insurance companies have announced plans to cover OTC purchase of the drug for their members.

View Comparison Table: Some Drugs for Maintenance Treatment of Opioid Use Disorder

Opioid use disorder is a chronic, relapsing disease with physical and psychiatric components. It is associated with economic hardship, social isolation, incarceration, increased rates of blood-borne infections such as HIV and viral hepatitis, adverse pregnancy outcomes, and increased mortality. According to the NIH, there were 80,411 deaths involving an opioid in the US in 2021, more than in any previous year. Several guidelines on the management of opioid use disorder are available; all recommend maintenance pharmacotherapy as the standard of care.

The FDA has approved the over-the-counter (OTC) sale of Narcan (Emergent), a nasal spray that delivers 4 mg of the opioid antagonist naloxone. Narcan nasal spray has been available by prescription since 2015 for emergency treatment of opioid overdose. Generic formulations of Narcan have also been approved; the manufacturers of these products will be required to switch them to OTC status and amend their labeling accordingly. Kloxxado, an 8-mg naloxone nasal spray, remains available only by prescription.

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

The FDA has approved a generic injectable formulation of the opioid antagonist nalmefene (Purdue) for the management of known or suspected opioid overdose. Revex, the reference product, was withdrawn from the market in 2008 for commercial reasons.

The FDA has approved a higher-dose injectable formulation of the opioid antagonist naloxone (Zimhi – Adamis) for emergency treatment of opioid overdose. A single IM or SC injection of the new formulation delivers 5 mg of naloxone; injectable formulations that deliver 0.4 mg or 2 mg of the drug have been available for years. Naloxone is also available in intranasal formulations for the same indication (see Table 1).

The FDA has approved a higher-dose intranasal naloxone formulation (Kloxxado – Hikma) for emergency treatment of opioid overdose. A single spray of the new formulation delivers 8 mg of naloxone; a formulation that delivers 4 mg per spray (Narcan) was approved in 2015.

Healthcare providers are often asked if drugs can be used past their expiration date. Because of legal restrictions and liability concerns, manufacturers do not sanction such use and usually do not comment on the safety or effectiveness of their products beyond the date on the label. Since our last article on this subject, more data have become available.

View Expanded Table: Some Drugs for Management of Opioid Withdrawal Symptoms

The FDA has approved lofexidine (Lucemyra – US WorldMeds/Salix), a centrally acting alpha₂ receptor agonist, to manage withdrawal symptoms in adults abruptly stopping opioid use. Available in the UK since 1992, lofexidine is the first nonopioid to be approved in the US for management of opioid withdrawal symptoms. Clonidine (Catapres, and generics), another central alpha₂ receptor agonist, has been used off-label for this indication for many years.

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.

The FDA has approved a subcutaneous (SC) extended-release formulation of the mu-opioid receptor partial agonist and kappa-opioid receptor antagonist buprenorphine (Sublocade – Indivior) for once-monthly treatment of moderate to severe opioid use disorder. Sublocade is the first injectable buprenorphine product to be approved in the US. Buprenorphine is also available in sublingual formulations with or without the opioid antagonist naloxone, in a buccal formulation with naloxone, and as a subdermal implant (Probuphine).

Opioid use disorder is a chronic, relapsing disease with both physical and psychiatric components. It is associated with economic hardship, social isolation, incarceration, increased rates of blood-borne infections such as HIV and viral hepatitis, adverse pregnancy outcomes, and increased mortality. According to the CDC, there were 33,091 deaths related to opioid overdose in the US in 2015, more than in any previous year. Several guidelines on the management of opioid use disorder have recently been published.

The FDA has approved subdermal implants of the partial opioid agonist buprenorphine (Probuphine – Titan) for maintenance treatment of opioid dependence in patients stabilized on low to moderate doses of transmucosal buprenorphine. Probuphine was designed to provide continuous low levels of buprenorphine for 6 months and to safeguard against illicit use of the drug.

The FDA has approved Xtampza ER (Collegium), a new extended-release, abuse-deterrent capsule formulation of oxycodone, for management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

A reader expressed concern that a statement in our article Naloxone (Narcan) Nasal Spray for Opioid Overdose (Med Lett Drugs Ther 2016; 58:1) might be misleading. We stated that heroin has a half-life of 2-6 minutes, which is correct, but heroin is a prodrug that is rapidly metabolized to 6-acetylmorphine and morphine. The risk of respiratory depression is related to those active metabolites, and it may persist well beyond the clearance of heroin from the blood.

The recent increase in deaths due to overdose of heroin and prescription opioids in the US has renewed interest in the opioid antagonist naloxone, particularly in making it available to first responders and to relatives and close friends of persons using heroin or taking prescription opioids. IV or IM administration by healthcare professionals is preferred, but peripheral venous access may be difficult to obtain in IV drug abusers, and exposure to their blood may be hazardous.

Development of abuse-deterrent opioid products, including reformulation of existing products, has become a priority for drug manufacturers and public health advocates. Three available opioid formulations, OxyContin (Purdue), Embeda (Pfizer), and Hysingla ER (Purdue), now include claims of abuse deterrence in their package inserts.

The FDA has approved a buccal film formulation of the partial opioid agonist buprenorphine combined with the opioid antagonist naloxone (Bunavail – BioDelivery Sciences) for maintenance treatment of opioid dependence. Sublingual tablet and film formulations of the same combination were approved earlier. The manufacturer of Bunavail claims that the new product is superior to sublingual formulations because of the convenience of buccal administration and better absorption into the blood, permitting use of lower doses.

A recent Medical Letter article reported renewed interest in the intranasal administration (off-label) of the opioid antagonist naloxone because of an increase in deaths from opioid overdose in the US.1 Now the FDA has approved a more practical alternative for emergency treatment of life-threatening opioid overdose in adults and children: a single-dose naloxone auto-injector (Evzio – Kaleo) for intramuscular or subcutaneous use.

Evzio will be available in kits containing two prefilled 0.4-mg auto-injectors with voice guidance and a "trainer" device that also has voice guidance, but does not contain medication or a needle. The manufacturer has not published a price for Evzio to date, but news reports indicate that each kit could cost hundreds of dollars, compared to about $20 for a standard 0.4-mg injectable dose of naloxone, which can be given intranasally.

1. Intranasal naloxone for treatment of opioid overdose. Med Lett Drugs Ther 2014; 56:21.

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The recent increase in deaths from heroin overdose in the US has led to renewed interest in the opioid antagonist naloxone, particularly in making it available as an intranasal spray to paramedics and possibly to relatives and close friends of heroin users. Intravenous (IV) administration is preferred, but peripheral venous access may be difficult to obtain in IV drug abusers, and exposure to their blood may be hazardous.

A new sublingual tablet formulation of the partial opioid agonist buprenorphine combined with the opioid antagonist naloxone (Zubsolv – Orexo) has been approved by the FDA for maintenance treatment of opioid dependence. Zubsolv tablets have relatively greater bioavailability than previously approved sublingual film (Suboxone) and sublingual tablet formulations of buprenorphine/naloxone and, according to an open-label survey, they taste better. The new tablets are smaller and dissolve faster than other tablet formulations, and they are individually sealed in child-resistant packaging.1

Buprenorphine is a Schedule III controlled substance that can be prescribed in an office setting by qualified physicians who register with the Substance Abuse and Mental Health Services Administration.2

Zubsolv is available as triangular tablets containing 1.4 mg of buprenorphine and 0.36 mg of naloxone and round tablets containing 5.7 mg of buprenorphine and 1.4 mg of naloxone, which achieve plasma concentrations of buprenorphine equivalent to those with the 2/0.5-mg and 8/2-mg strengths of other buprenorphine/naloxone tablets. A package of Zubsolv 5.7/1.4-mg tablets costs the same ($211) as a box of Suboxone 8/2-mg films. A bottle of generic buprenorphine/naloxone 8/2-mg tablets costs $250.3

1. A Fischer et al. Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers. Drug Dev Ind Pharm 2013 Oct 7 (epub).

2. Buprenorphine: an alternative to methadone. Med Lett Drugs Ther 2003; 45:13.

3. Approximate wholesale acquisition cost (WAC) of 30 tablets or films. Source: $ource® Monthly (Selected from FDB MedKnowledge™) October 5, 2013. Reprinted with permission by FDB, Inc. All rights reserved. ©2013. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices may be higher.

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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

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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Every pharmaceutical drug is a dose-dependent poison. This article describes the clinical presentation and treatment of some dangerous overdoses commonly reported in adults.

The FDA has approved the marketing of buprenorphine in sublingual tablets (Reckitt Benckiser) both alone (Subutex) and with naloxone (Suboxone) for treatment of opioid dependence. Previously available only for parenteral use in treatment of pain (Buprenex, and others), it offers an alternative to methadone (Dolophine, and others), which is now often abused (New York Times, February 9, 2003; page 1). As a schedule III narcotic, buprenorphine will be subject to fewer prescribing restrictions than a schedule II drug such as methadone (MJ Kreek and FJ Vocci, J Subst Abuse Treat 2002; 23:93).w1150a

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.

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.

Naltrexone (ReVia -DuPont Pharma), a long-acting oral opioid antagonist previously marketed for treatment of opioid dependence under the trade name Trexan, was recently approved by the US Food and Drug Administration (FDA) for treatment of alcohol dependence. The new trade name will now also be used for the old indication.

Butorphanol tartrate, a synthetic opioid agonist-antagonist analgesic previously available for injection, is now being marketed as a nasal spray (Stadol-NS - Mead Johnson). The spray was approved by the US Food and Drug Administration (FDA) for any type of pain for which an opioid analgesic is appropriate, but the manufacturer is emphasizing use for treatment of migraine headache and postoperative pain. Drugs for pain were reviewed in the Medical Letter, volume 35, page 1, January 8, 1993.

The well-publicized recovery from paralysis of a professional football player has recently focused attention on the growing use of drugs to minimize the effects of spinal cord injury. Methylprednisolone sodium succinate (Solu-Medrol - Upjohn), commercially available in the USA for intravenous treatment of transplant rejection and various inflammatory and auto-immune disorders, and GM-1 ganglioside, commercially available in Italy (Sygen - Fidia) but not in the USA, are now widely used in patients with spinal cord injury.

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.

Dezocine (Dalgan - Astra), a new synthetic opioid agonist/antagonist structurally related to pentazocine (Talwin), was recently approved for parenteral use as an analgesic by the US Food and Drug Administration.

Some commonly used systemic drugs that may cause pulmonary toxicity are listed in the table below. These adverse effects may sometimes be difficult to distinguish from the underlying disease (JAD Cooper, Jr et al, Am Rev Respir Dis, 133:321, 488, 1986). Pulmonary effects that are part of a generalized reaction or are indirect effects of drugs - on respiratory muscles, for example, or on the immune system - are not included here.