Special K for breakfast: Is ketamine a solution for sickle cell pain?

It’s 4am in the emergency department, and you’ve finally reached a lull in the onslaught of patients after having finally successfully bailed out the flood from the afternoon. An individual very familiar to you and the rest of the department pops up on the board. Despite the risk of crashing your computer due to the enormous size of this patient’s chart, you assign yourself and take the plunge. Chief complaint: Sickle cell pain.

You approach the patient, who tells you her pain is mostly in her back and legs. No, she hasn’t been short of breath, and no, she hasn’t had a fever. She answers your questions patiently but eventually cuts to the chase, “Can I have my dose of 6mg Dilaudid and 50 mg of Benadryl?”

We’re all aware of opioid epidemic that’s currently raging, presumably as a result of patient satisfaction metrics and the medical community’s heavy-handed prescribing over the past few decades. While this is a problem for the treatment of acute and chronic conditions across the board, the nature and course of sickle cell disease predisposes these patients to dependence and makes it complicated to address responsibly. We all know to start with NSAIDS, but for patients who have been prescribed opioids from a young age, this sometimes doesn’t cut the mustard.

Is there another way?

There are many alternatives for acute pain control: IV lidocaine, IV acetaminophen, propofol, and even dexmedetomidine (See Dr. Nguyen’s excellent lecture). One emergency department in New Jersey has even employed “energy healing and a wandering harpist” to avoid opioid prescriptions. Although these are all reasonable regimens, the medications listed above are administered intravenously, which may be a challenge in sickle cell patients with notoriously difficult venous access. (And there’s a certain lack of evidence that energy healing and the harp are effective as monotherapy.)

Easing suffering one chord at a time.

Ketamine, however, has been tested intranasally (IN) and found to be effective. One double-blinded RCT on 90 trauma patients in the ED compared either 1 mg/kg IN ketamine, 0.1 mg/kg IV morphine, or 0.15mg/kg IM morphine and found that the three regimens had similar onset and effectiveness at relieving pain. No adverse events were reported.^[1] Although a small study, IN ketamine’s utility in treating acute pain in the ED has been corroborated by other observational studies.^[2]^,[3]

Another RCT on 20 patients on opioid maintenance therapy for chronic pain found self-administered IN ketamine to be more effective at placebo at controlling breakthrough pain¹; in this population, no patients receiving ketamine required their ‘normal’ rescue opioid medication. However, 35% of the placebo group had to reach for additional opioids. No adverse events were reported. If you consider sickle cell pain to be acute-on-chronic, ketamine may be something to consider.

It is worth noting that although we’ve concentrated on IN route above because of its implications for patients with difficult vascular access (i.e. sickle cell patients), IV ketamine at 0.1 mg/kg – a subdissociative dose – has been shown to be effective for pain in the ED when given IV compared to morphine at a dose of 0.3 mg/kg.^[4] A meta-analysis and review by Motov et. al. on the subject supports its use at this dose.^[5]

Sickle Cell Specifics

Before you pull the trigger on ordering that ketamine and get the inevitable call from pharmacy (and then explain its indication to the nurse), has it been studied in sickle cell disease, specifically?

Unfortunately, there is really no consensus on how to manage refractory pain in sickle cell patients – a Cochrane review from 2009^[6] found that studies examining the correct pain regimen were underpowered, and the authors were unable to provide a recommendation.

There’s a right way to administer intranasally. And then there’s the other way.

The data on sickle cell disease is confined to case reports,^[7]^{,[8],[9],[10],[11]} mostly from inpatient teams that had success with ketamine when opioids failed. However, in combination with the data on its use in both acute and chronic pain, I would argue that it is a reasonable alternative to opioids. A pediatric anesthesia review^[12] on the subject agrees.

But what about the abuse potential?

While it’s true ketamine is used recreationally, it’s important to note that we’re not currently in the throes of history’s greatest ketamine epidemic (unlike opioids). A 2016 review^[13] acknowledges that ketamine abuse and tolerance does occur, but contrary to opioids, it tends to be more in the specific setting of recreational use, and users do not seem to develop the same level of dependence. The American Association of Poison Control Centers recorded only 327 exposures to ketamine in 2014, only 1 of which was fatal^[14]. Furthermore, no formal withdrawal syndrome has been described.

Get ‘em while they’re young

As an editorial aside, many sickle cell patients seem to have developed tolerance to opioids as a result of frequent hospitalizations, many at a young age, resulting in dependence that may be related to but is separate from sickle cell disease itself. Perhaps there should be some discourse about the long-term consequences that these patients face as a result of opioid prescriptions – should we be encouraging the use of a regimen that utilizes more opioid-sparing agents for sickle cell patient at an younger age?

Less abuse potential than some alternatives

Wrap Up

Subdissociative-dose ketamine has been shown to be safe and effective at treating chronic and acute pain. Although specific evidence regarding its use in sickle cell disease is lacking beyond case reports, it has the advantage of intranasal (rather than parenteral) administration in the difficult venous access-patient and has a more favorable profile with regards to abuse. It requires adequate prospective study to reach a more concrete conclusion, but perhaps it’s time to consider 1 mg/kg IN ketamine in sickle cell patients as an opioid-alternative to reduce the risk of dependence.

^[1] Shimonovich S, Gigi R, Shapira A, et al. Intranasal ketamine for acute traumatic pain in the Emergency Department: a prospective, randomized clinical trial of efficacy and safety. BMC Emergency Medicine 2016;16(1).

^[2] Andolfatto G, Willman E, Joo D, et al. Intranasal Ketamine for Analgesia in the Emergency Department: A Prospective Observational Series. Academic Emergency Medicine 2013;20(10):1050–4.

^[3] Shrestha R. Intranasal ketamine for the treatment of patients with acute pain in the emergency department. World Journal of Emergency Medicine 2016;7(1):19.

^[4]Motov S, Rockoff B, Cohen V, Pushkar I, et. al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Annals of Emergency Medicine 2015; 66(3)222.

^[5] Motov S, Rosenbaum S, Vilke G, Nakajima Y. Is there a role for intravenous subdissociative-dose ketamine administered as an adjunct to opioids or as a single agent for acute pain management in the emergency department? The Journal of Emergency Medicine 2016;6(51)752

^[6] Dunlop R, Bennett KC. Pain management for sickle cell disease in children and adults. Cochrane Database of Systematic Reviews 2014

^[7] Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Annals of Hematology 2013;93(5):769–71.

^[8] Tawfic QA, Faris AS, Kausalya R. The Role of a Low-Dose Ketamine-Midazolam Regimen in the Management of Severe Painful Crisis in Patients With Sickle Cell Disease. Journal of Pain and Symptom Management 2014;47(2):334–40.

^[9] Meals CG, Mullican BD, Shaffer CM, Dangerfield PF, Ramirez RP. Ketamine Infusion for Sickle Cell Crisis Pain in an Adult. Journal of Pain and Symptom Management 2011;42(3).

^[10] Jennings CA, Bobb BT, Noreika DM, Coyne PJ. Oral Ketamine for Sickle Cell Crisis Pain Refractory to Opioids. Journal of Pain & Palliative Care Pharmacotherapy 2013;27(2):150–4.

^[11] Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of Low-dose Ketamine Infusion for Pediatric Patients With Sickle Cell Disease-related Pain. The Clinical Journal of Pain 2010;26(2):163–7.

^[12] Neri CM, Pestieau SR, Darbari DS. Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. Pediatric Anesthesia 2013;23(8):684–9.

^[13] Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M. A Review Of Ketamine Abuse And Diversion. Depression and Anxiety 2016;33(8):718–27.

^[14] Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015;53(10):962-1147