Intranasal ketamine as an analgesic agent for acute pain management in emergency department: A literature review

Abdolghader Pakniyat, Morteza Qaribi, Dorin Rahnama Hezaveh, Ali Abdolrazaghnejad

1Department of emergency Medicine, Faculty of Medicine, Kurdistan University of medical sceinces, Sanandaj, Iran

2Department of Emergency Medicine, School of Medicine, Arak University of Medical Sciences, Arak, Iran

3School of Medicine, Medical University of Lublin, Lublin, Poland

4Department of Emergency Medicine, Khatam-Al-Anbia Hospital, Zahedan University of Medical Sciences, Zahedan, Iran

Keywords:Administration Intranasal Emergency department Ketamine Pain management Review literature

ABSTRACT Ketamine is a well-known dissociative anesthetic agent, and has been used over 50 years.Intranasal pathway is a mucosal way for absorbing agents to directly affect in brain via olfactory sheets, bypassing first pass metabolism and the blood brain barrier. The current uses of intranasal ketamine as an analgesic agent for acute pain management in emergency department are discussed in this review article. Using “ketamine”, “pain or analgesia”, and“intranasal” as keywords, a search of google scholar, Pubmed, web of science, and Medline database from 1970 until 2017 was performed. Finally, from 1 204 papers extracted via primary search, 1 088 papers were omitted and finally 10 studies were considered for further assessment. There were four observational studies, one case series and report and 5 clinical trials. Ketamine was used for acute pain control due to musculoskeletal trauma, burns, and painful procedures. A total of 390 cases were included in these studies. The studies used ketamine with doses ranging 0.45-1.25 mg/kg via intranasal pathway. Intranasal ketamine provides relatively rapid, well tolerated, and clinically significant analgesia for emergency department patients. Considering the lack of adequate studies and undetermined intranasal dose, it is better to conduct further high quality investigation in both adults and pediatrics.

1. Introduction

Ketamine is a well-known dissociative anesthetic agent that mediated its effects mainlyviablockade of N-methyl-D-aspartate and hyperpolarisation-activated-cyclic-nucleotide receptors[1]. For over 50 years, it has been used in various ways[1-3]. It is likely that it is a very useful agent for conducting procedural sedation and analgesia in emergency department (ED)[4-6]. Despite using as an analgesic agent in management of chronic pain, but it is not routinely used for acute pain management of ED due to its potentially side effects such as dissociation and emergence phenomenon[7,8].Due to overcrowding and lack of human and facilities resources in EDs, using a safe drug with minimal side effects is crucial.Recent evidence proved efficacy of low dose ketamine in this regards, although it needs further investigation[9-11]. Each drug has some different pathway of administration. Intranasal pathway is a mucosal way for absorbing agents to directly affect in brainviaolfactory sheets, bypassing first pass metabolism and the blood brain barrier[12]. Accordingly, the current uses of intranasal ketamine as an analgesic agent for acute pain management of ED are discussed in this review article.

2. Evidence acquisition

All observational and randomized controlled trials that surveyed the use of intranasal ketamine as an analgesic agent in the emergency setting were eligible for assessing in this study. Using “ketamine”,“pain or analgesia”, and “intranasal” as keywords, a search of google scholar, Pubmed, web of science, and Medline database from 1970 until 2016 was performed. The searching process was performed with two independent investigators. All papers and additional references from their citation were also included.Initially the abstracts were screened regarding the use of intranasal ketamine as an analgesic agent for acute pain management in both prehospital and ED setting. No age limit was considered and both adult and pediatric studies were included. Papers that used ketamine through other pathway than intranasal published in non-English languages, animal studies, and review articles were excluded. Nonavailable full text, duplicated studies, and unpublished ones were eliminated. Evaluation was performed independently by 4 reviewers and validated scales were using pain measurement tools and also mentioning side effects were in the studies. The results were summarized and presents in Tables.

3. Results

Finally, from 1 204 papers extractedviaprimary search, 1 088 papers were omitted and finally 10 studies were considered for further assessment. There were four observational studies, one case series and report and 5 clinical trials including 4 randomized, 1 nonrandomized, 4 blinded, and 1 non-blinded one (Figure 1). Ketamine was used for acute pain control due to musculoskeletal trauma,burns, and painful procedures. A total of 631 cases were included in these studies. The studies used ketamine with doses ranging 0.45 -1.25 mg/kgviaintranasal pathway.

Table 1 shows the characteristics and summery of the clinical trial studies included in the current review. Clinical trial studies showed acceptable analgesia with ketamine with no differences compared with other analgesic agents[13-15]. Table 2 shows the characteristics and summery of the non-clinical trial studies included in the current review. The observational studies and case reports concluded analgesic effect of ketamine without major side effects[19-22]. Summary of reported side effects in the studies included in the current review were reported in Table 3. All side effects were minor and transient.

Figure 1. Fowchart of search strategy and paper extraction in current review.

Table 1 Characteristics and summery of clinical trial studies in current review.

Table 2 Characteristics and summery of non-clinical trial studies in current review.

Table 3 Summery of reported side effects in studies of current review.

4. Discussion

Based on the findings of current review, there are acceptable analgesic effects for intranasal ketamine. However, since all studies were included without consideration age, clinical situation and dosage, it would not be possible to determine definite evidence regarding use of intranasal ketamine as an analgesic agent for acute pain management of ED.

Bioavailability of ketamine through intranasal pathway is 45%-55%[13]. It was reported that intranasal ketamine is detectable in blood 2 min after administration and its maximum concentration would be at 30 min later, and provides sufficient analgesia up to 1 h[24]. When used in combination with other drugs, low dose intranasal ketamine could result in reducing the dose of the other agents. It is particularly useful in opium-addicted patients[14,20,21,25].Co-administration of other analgesic agents such as in the study of Graudinset althat patients received ibuprofen, it may be affected on study results[14].

All studies were conducted on traumatic patients, and supported intranasal ketamine sufficient analgesic effect 30 min later, although available data regarding its use in adult is still limited[14-22,16,23].Clinical trials showed no difference between the studied groups regarding pain control. Reported side effects were minor and transient and did not need any intervention[14-16].

Ketamine was used for painful procedural sedation. Nejatiet alshowed that intranasal ketamine facilitated nasogastric tube insertion, without increasing the rate of vomiting[15]. In the study of Neilsenet al, sufentanil/ketamine nasal spray provided rapid onset of analgesia for a variety of painful procedures, so intranasal ketamine is an acceptable choice for suturing, intravenous line insertion andetc[16].

There were some differences among studies regarding how the drug was administered into nostril, dripping with a syringe or using a spray device. Better absorption occurs while the agent is sprayed into nasal cavity that provided wider mucosal surface area for absorption[19,22].

Nasal ketamine may be used in cases where there is no need for venipuncture of peripheral vessels, especially in crowded EDs and in prehospital situation, where venipuncture is difficult[18,26].

The authors believe that intranasal ketamine is safe and does not need close monitoring, but in cases with severe pain in crowded ED it may be not suitable or possible to wait 30 min to achieve sufficient analgesic effect. Use of ketamine in combination with low dose of other analgesic agents would be a better decision. Intranasal pathway is a rapid and needleless approach that decline the risk of transmission of blood-borne infections in a stressful situation of out of hospital such as bad weather condition and dangerous environment, as well in cases that have not an intravenous access or does not need to insert intravenous line like an isolated orthopedic trauma, intranasal rout would be preferable.

5. Conclusion

Intranasal ketamine provides relatively rapid, well tolerated, and clinically significant analgesia for ED patients. Considering the lack of adequate studies and undetermined intranasal dose, it is better to conduct further high quality investigation in both adults and pediatrics.

Conflict of interest statement

The authors report no conflict of interest.