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Three Part Question

In a [patient with an acute allergic reaction] does [a sublingual adrenaline tablet as compared to an intramuscular injection] work [better at reversing symptoms and preventing adverse effects of adrenaline?]

Clinical Scenario

A 34 year Jamaican man attended the Emergency Department after having his back tattooed. He had gross urticaria and swelling to his lips and face. His tongue was large and inflamed. You looked at the tongue and wondered if you could put a tablet of adrenaline under it and whether it would work as well as an intramuscular injection. You remember from your student days that sublingual and rectal absorption of tablets is much faster than intramuscular injection.

Search Strategy

Medline 1950 to February week 4 2009
"((epinephrin$.MP.) OR (adrenalin$.MP.)) AND ((tablet$.MP.) OR (sublingual$.MP.))"

Search Outcome

160 papers were found. Two reviews discussed sublingual adrenaline as a potential alternative to intra-muscular injection. Three studies were directly relevant (all by the same group of researchers). One case report seemed interesting.

One paper was relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Rawas-Qalaji MM et al (1) 2006 Canada	5 New Zealand white rabbits (mean weight 4.8kg). Each rabbit was administered a 10mg, 20mg, 40mg and 0mg (placebo) adrenaline tablet sublingually and an IM injection of 0.3mg adrenaline to the thigh on 5 different study days at least 4 weeks apart. Blood samples were taken from an ear artery at regular intervals until 180 minutes after drug administration.	Prospective controlled 5 way cross-over study.	Maximum plasma adrenaline concentration (Cmax) (mean +/- SEM)	40mg sublingual adrenaline (31.0 +/- 13.1 ng/mL), 0.3 mg IM (50.3 +/- 17.1 ng/mL) NS. 10mg and 20mg tablets gave significantly lower Cmax than 0.3mg IM.	Small numbers result in large SEMs, so that although there are differences in means they do not reach statistical significance.
			Time of Cmax (mean +/- SEM)	10mg (37 +/- 11 min), 20mg ( 31 +/- 9 min), 40mg (9 +/- 2 min), 0.3mg IM (21 +/- 5 min) NS.
			Area under the plasma adrenaline concentration versus time curve (AUC) (mean +/- SEM)	40mg sublingual adrenaline (1861 +/- 537 ng/mL/min), 0.3 mg IM (2431 +/- 386 ng/mL/min) NS. 10mg and 20mg tablets gave significantly lower AUCs than 0.3mg IM.
Rawas-Qalaji MM et al. (2) 2006 Canada	5 New Zealand white rabbits (mean weight 4.7kg). Each rabbit was administered 4 different tablet formulations of 40mg adrenaline sublingually (using different excipients labelled A, B, C and D) and an IM injection of 0.3mg adrenaline to the thigh on 5 different study days at least 4 weeks apart. Blood samples were taken from an ear artery at regular intervals until 180 minutes after drug administration.	Prospective controlled 5 way cross-over study.	Area under the plasma adrenaline concentration versus time curve (AUC) (mean +/- SEM)	Formulation A 40mg sublingual adrenaline (1861 +/- 537 ng/mL/min), 0.3 mg IM (2431 +/- 386 ng/mL/min) NS. Formulations B, C and D gave significantly lower AUCs than 0.3mg IM.	Small numbers result in large SEMs, so that although there are differences in means they do not reach statistical significance.
			Maximum plasma adrenaline concentration (Cmax) (mean +/- SEM)	Formulation A 40mg sublingual adrenaline (31.0 +/- 13.1 ng/mL), 0.3 mg IM (50.3 +/- 17.1 ng/mL) NS. Formulations B, C and D gave significantly lower Cmax than 0.3mg IM.
			Time of Cmax (mean +/- SEM)	Formulation A (9 +/- 4 min), formulation B (28 +/- 10 min), formulation C ( 27 +/- 9 min), formulation D (14 +/- 4 min ), 0.3mg IM (21 +/- 11 min) NS.
Rothrock et al. 1993 USA	7 month old girl in cardio-respiratory arrest. Pre-hospital intubation and IV cannulation unsuccessful. Resuscitation drugs administered 13 minutes after cardio-respiratory arrest by sublingual injection.	Case report.	Return of spontaneous circulation.	After sublingual injection of adrenaline (1.5mg) and atropine (0.15mg)	No evidence that the sublingual injection of adrenaline and atropine was responsible for the return of spontaneous circulation.
			Survival	Patient died in the Emergency Department 58 minutes after initial cardio-respiratory arrest.
Gu et al. 2002 Canada	6 New Zealand white rabbits (mean weight 4.2kg). Each rabbit received a 2.5mg and a 10mg adrenaline tablet sublingually, an IM injection of 0.03mg adrenaline and an IM injection of 0.9% saline (0.3mL) to the thigh on 4 different study days at least 4 weeks apart. Blood samples were taken from an ear artery at regular intervals until 180 minutes after drug administration.	Prospective randomised controlled cross-over study.	Maximum plasma adrenaline concentration (Cmax) (mean +/- SEM)	2.5mg adrenaline (2369 +/- 392 pg/mL), 10 mg adrenaline (10836 +/- 2234 pg/mL), IM adrenaline (6445 +/- 4233 pg/mL), saline (endogenous adrenaline) (518 +/- 142 pg/mL). Cmax for 10mg sublingual adrenaline did not differ significantly from Cmax for IM adrenaline.	Small numbers result in large SEMs, so that although there are differences in means they do not reach statistical significance.
			Time of Cmax (mean +/- SEM)	2.5mg adrenaline (20.8 +/- 5.7 min), 10mg adrenaline (21.7 +/- 5.4 min), IM adrenaline (15.8 +/- 4.7 min). Tmax for sublingual adrenaline did not differ significantly from Tmax for IM adrenaline.

Comment(s)

Although intramuscular adrenaline is an effective treatment for anaphylaxis, out-of-hospital administration by auto injector is not without problems (not always carried, not always used properly, and sometimes not used at all or too late). A non-injectable form of adrenaline, such as a tablet, would be much easier to use. Unfortunately adrenaline is rapidly conjugated and oxidised in the wall of the gastrointestinal tract making oral administration unrealistic. An alternative would be the sublingual route. Many drugs, in liquid form, can already be delivered by the sublingual route (for example, nitrates, nifedipine, captopril, benzodiazepines, and opioids). The studies assessed used a rabbit model as rabbits are adrenaline-tolerant, so that human doses can be used without adverse effects. It seems that adrenaline can be administered sublingually in the rabbit. A 40mg tablet may give fairly similar maximum plasma concentrations, time of maximum concentration and AUC as an IM injection of 0.3 mg. However, the excipient used does make a difference. Different manufacturing characteristics have been studied to determine optimal dimensions (Rawas-Qalaji et al 2007) and the effect of different adrenaline doses on tablet characteristics (Rawas-Qalaji et al 2006 (3)).

Clinical Bottom Line

Epinephrine tablets are a novel fast disintegrating formulation. They may be a feasible alternative to intramuscular adrenaline in the future. Until clinical trials have shown this to be a safe and effective route of administation of adrenaline the intramuscular route should continue to be used.

References

1. Rawas-Qalaji MM, Simons FER, Simons KJ. Sublingual epinephrine tablets versus intramuscular injection of epinephrine: dose equivalence for potential treatment of anaphylaxis Journal of Allergy and Clinical Immunology 2006; 117 (2): 398-403
2. Rawas-Qalaji MM, Simons FER, Simons KJ. Epinephrine for the treatment of anaphylaxis: do all 40 mg sublingual epinephrine tablet formulations with similar in vitro characteristics have the same bioavailability? Biopharmaceutics & Drug Disposition 2006: 27 (9): 427-435.
3. Rawas-Qalaji MM, Simons FER, Simons KJ. Fast-disintegrating sublingual tablets: effect of epinephrine load on tablet characteristics AAPS PharmSciTech. 2006: 7 (2): Article 41, ppE1-E7.
4. Rawas-Qalaji MM, Simons FER, Simons KJ. Fast-disintegrating sublingual epinephrine tablets: effect of tablet dimensions on tablet characteristics. Drug Development & Industrial Pharmacy 2007: 33 (5): 523-530
5. Rothrock SG, Green SM, Schafermeyer RW, Colucciello SA. Successful resuscitation from cardiac arrest using sublingual injection of medication delivery. Annals of Emergency Medicine 1993: 22 (4): 751-753
6. Gu X, Simons KJ, Simons ER. Is epinephrine administration by sublingual tablet feasible for the first-aid treatment of anaphylaxis? A proof-of-concept study. Biopharmaceutics & Drug Disposition 2002: 23: 213-216