Background:

Sickle Cell Disease  (SCD) is an inherited blood disorder that affects about 4.4 million people worldwide, with an additional 43 million with sickle cell trait. The African region has the highest prevalence with an estimated 200,000 babies born with sickle cell disease every year. In the US, the number of people living with sickle cell disease is approximately 100,000 and it mostly affects Americans of African descent.

Signs and symptoms of SCD include red blood cell (RBC) sickling; chronic hemolytic anemia (premature red cell destruction); episodic vaso-occlusion (obstruction of blood flow), acute and cumulative organ damage that manifests as stroke, acute chest syndrome, sickle lung disease, pulmonary hypertension, nephropathy and end-stage renal disease; and other chronic morbidities. Patients with SCD have a high health care utilization (over $1 billion/year in healthcare costs in the United States), and a median life-expectancy of only about 45–58 years, compared to the life expectancy of 78.2 years overall in the United States

Vaso‐occlusion is the most common manifestation and can lead to an acute, painful crisis (sickle cell crisis, vaso‐occlusive crisis (VOC) or vaso‐occlusive episode). Pain occurs most in the joints, extremities, back or chest, but it can occur anywhere and can last for several days or weeks. The bone and muscle pain experienced during a sickle cell crisis can be acute and recurrent.

VOC is treated with both pharmacological drugs such as opioid analgesics, non‐opioid analgesics, combinations of drugs and non‐pharmacological approaches, such as relaxation, hypnosis, heat, ice and acupuncture.  These therapies, have been used in combination to rehydrating the patient.

Opioid analgesics is the primary choice of pain relief in VOC management. These include codeine, hydrocodone/paracetamol (hydrocodone/acetaminophen), hydrocodone/ibuprofen, oxycodone (and with codeine), morphine, hydromorphone, oxymorphone, methadone, diamorphine and fentanyl. Opioids are usually, administered as intravenous (IV) morphine every four to six hours. Also, oral opioids are prescribed after a VOC episode.  The half‐life of  most analgesic opioids is two to four hours, except for methadone, propoxyphene and meperidine, which can be one to several days. The standard dosing  with opioids, is normally every four to six hours.  In most cases dosing is reduced to every 2hours because some people develop tolerance to opioids. The combination of an opioid with  another pain medication with a different mechanism of action such as with diclofenac or paracetamol  (Tylenol) will reduce the use of an opioid to a minimum. The adverse effects of analgesic opioids include: respiratory depression, constipation, vomiting, nausea, pruritus and hives, addiction, and withdrawals.

Another group of  drugs for managing a VOC are the  non‐opioid analgesics. These include: paracetamol (Tylenol), non‐selective cyclo‐oxygenase (COX) inhibitors (aspirin (acetylsalicylic acid), ibuprofen, naproxen and ketorolac) and selective COX‐2 inhibitors (celecoxib).  Of these, non‐steroidal anti‐inflammatory drugs (NSAIDs), paracetamol, diclofenac and ketorolac,  are commonly used for mild‐to‐moderate pain either alone or in combination with opioid analgesia. The adverse effects of NSAIDs include gastrointestinal complications. Precautions should be taken when administering to  people with a history of renal failure, bleeding tendencies, asthma or peptic ulcers. Tylenol is administered orally at a dosage of 200 mg to 500 mg every four to six hours until an acceptable pain relief has been attained. High dose and long use of Tylenol can lead to  liver failure.

Other pharmacotherapeutic drugs used in the management of sickle cell crisis, include buprenorphine and buprenorphine/naloxone(partial agonists ); pentazocine, nalbuphine and butorphanol ( mixed agonist‐antagonists) and hydroxyurea.

Objective:

The aim of this study, is to search the literature for drugs that are used in the management of sickle cell pain arising from VOC for safety and efficacy across the age group.

Method:

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, Embase via Ovid and Google Scholar from January 1, 2000 to  September 2022. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. We included studies on adolescents and adults with sickle cell disease.

Results:

Most of the studies, compared the effect of opioid, non-opioid and a combination of opioid/non-opioid on the management of sickle cell crisis as:

• Non‐steroidal anti‐inflammatory drugs (NSAID) compared with placebo: No data was collected to show pain relief of 50% or 30% or greater.
• Opioids compared with placebo:  No data was collected to show pain relief of 50% or 30% or greater.
• Morphine (IV) with sustained release oral morphine: This study was carried out in children and young adults. There was no significant difference in the      mean overall pain scores, frequency of rescue analgesia, and frequency/severity of adverse‐effects.
• Parenteral morphine  with butorphanol: This study was in adult patients treated in an emergency department. There was no significant difference in pain or pain relief scores, discharge rate and adverse effects.

Conclusion:

From our review, there is no single or a combination of pharmacological interventions that completely stop  pain during sickle cell crisis.

References:

Akindele, A. O., Jalkh, A. P. C., Eastmond, A. K., Shetty, C., Rizvi, S. M. H. A., Sharaf, J., … & Chavarria, Y. Y. (2022). Treatment Options That Reduce the Duration of Sickle Cell Vaso-Occlusive Crises: A Systematic Review. Cureus Journal of Medical Science, 14(8).

Cooper TE, Hambleton IR, Ballas SK, Johnston BA, Wiffen PJ. Pharmacological interventions for painful sickle cell vaso-occlusive crises in adults. Cochrane Database Syst Rev. 2019 Nov 14;2019(11):CD012187. doi: 10.1002/14651858.CD012187.pub2. PMID: 31742673; PMCID: PMC6863096.

Kavanagh, P. L., Fasipe, T. A., & Wun, T. (2022). Sickle cell disease: a review. JAMA, 328(1), 57-68.