Table 3.
Summary of the debate over IN and nonmedical naloxone
| Objections to IN naloxone | Responses to objections |
|---|---|
| The results from ambulance-based studies indicate that not all opioid overdose victims respond to IN naloxone, with some needing a rescue dose of IM or IV naloxone. Emergency care with an IN naloxone kit is limited by the absence of injectable naloxone as a backup25,31 | While IN naloxone may require a second dose more frequently, this alone should not preclude its nonmedical or take-home use.26 The FDA required Narcan Nasal Spray to be marketed in a two-pack configuration, ensuring that a second dose would be available in the event of an inadequate response to the first dose50 |
| Clinicians should prescribe take-home naloxone only as one of its formally approved formulations, since the reliability of absorption and effectiveness of the improvised nasal spray remains uncertain25 | Providers may still choose to recommend or provide off-label products even when approved products are available, because of the cost–benefit balance30 The lack of availability of “any” naloxone is a much greater threat to opioid users than the lack of availability of formally approved products28 |
| Progress with basic pharmacokinetic study of IN naloxone has been slow, with the only peer-reviewed pharmacokinetic study55 reporting extremely poor bioavailability (4%) for nasal naloxone25,31 | In addition to the cited study,55 which some consider is flawed by use of excess intranasal delivery volumes,24,25 more recent pharmacokinetic studies of formulations exhibiting much higher bioavailability are described in patents,52,53 FDA reports,50 and a peer-reviewed paper51 |
| Unapproved IN naloxone at 1 mg/mL may be inadequate for efficacy, compared to 0.4 mg IM injectable naloxone25,31 | Opioid overdose mortality was reduced by almost 50% in areas where 1 mg/mL naloxone nasal spray was accessible, compared to areas with no access46 |
| Wherever possible, clinicians should prescribe medications for use by the approved route of proven and highest effectiveness (i.e., IM as opposed to IN naloxone)25 | The broader public is considered to have low acceptance for needles, with nasal spray being much more palatable for nonmedical use28 Needlestick injuries to rescuers represent a serious risk of blood-borne infections, including HIV and hepatitis,8 a risk that is eliminated with IN naloxone |
| Despite the FDA approval of naloxone nasal spray, there are persistent concerns:3 | |
| 1. IN naloxone has historical nonresponse rates of between 9% and 26%31 | 1. Bioequivalency testing of Narcan IN naloxone demonstrated plasma levels that exceeded 0.4 mg IM plasma levels at all time points, starting at 2.5 min, with a similar time to maximum plasma concentration compared to IM naloxone, with levels exceeding the 0.4 mg IM peak plasma level for over 2 h50,51 This historical rate estimate is from studies of the off-label improvised nasal spray, inapplicable to the FDA-approved IN formulation. Also, even a lower limit of response rate of 74%–91% is better than the alternative without any naloxone |
| 2. Nonmedical use and reliance on IN naloxone may substitute for or delay use of emergency medical services and availability of naloxone injection | 2. Distributors of off-label IN naloxone generally provide training, including instructions to immediately contact EMS after dosing;46 approved IN naloxone kits provide the same instructions54 |
| 3. There is still uncertainty about dose adequacy and comparability of nasal naloxone to injectable formulations | 3. Bioequivalence to injectable naloxone has been demonstrated for FDA-approved IN Narcan50,51 |
| 4. At a practical level, there are uncertainties about the effectiveness of a nasal spray (e.g., the spray device is limited by possible poor functioning in a horizontal position) | 4. The ability of IN naloxone sprays to operate in a horizontal position has already been established for both improvised42 and approved50,51 IN spray devices |
| 5. IN naloxone effectiveness may be limited by the impact of compromised nasal mucosa, for example, chronic ulceration from nasal drug use snorting | 5. Compromise of the normal barrier function of the nasal mucosa would tend to increase drug penetration, with naloxone being more rather than less effective94 |
| 6. Effectiveness may be limited by nasal obstruction from vomit, precluding IN administration | 6. Although a theoretical concern, nasal obstruction from vomit has not been reported as a significant problem in the substantial literature of case studies of IN naloxone60 |
Abbreviations: FDA, US Food and Drug Administration; IM, intramuscular; IN, intranasal; IV, intravenous.