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Meta-Analysis
. 2019 Nov 14;2019(11):CD012187.
doi: 10.1002/14651858.CD012187.pub2.

Pharmacological interventions for painful sickle cell vaso-occlusive crises in adults

Tess E Cooper  1 , Ian R Hambleton  2 , Samir K Ballas  3 , Brydee A Johnston  4 , Philip J Wiffen  5
Affiliations
Meta-Analysis

Pharmacological interventions for painful sickle cell vaso-occlusive crises in adults

Tess E Cooper et al. Cochrane Database Syst Rev. .

Abstract

Background: Sickle cell disease (SCD) is a group of inherited disorders of haemoglobin (Hb) structure in a person who has inherited two mutant globin genes (one from each parent), at least one of which is always the sickle mutation. It is estimated that between 5% and 7% of the world's population are carriers of the mutant Hb gene, and SCD is the most commonly inherited blood disorder. SCD is characterized by distorted sickle-shaped red blood cells. Manifestations of the disease are attributed to either haemolysis (premature red cell destruction) or vaso-occlusion (obstruction of blood flow, the most common manifestation). Shortened lifespans are attributable to serious comorbidities associated with the disease, including renal failure, acute cholecystitis, pulmonary hypertension, aplastic crisis, pulmonary embolus, stroke, acute chest syndrome, and sepsis. Vaso-occlusion can lead to an acute, painful crisis (sickle cell crisis, vaso-occlusive crisis (VOC) or vaso-occlusive episode). Pain is most often reported 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 is both acute and recurrent. Key pharmacological treatments for VOC include opioid analgesics, non-opioid analgesics, and combinations of drugs. Non-pharmacological approaches, such as relaxation, hypnosis, heat, ice and acupuncture, have been used in conjunction to rehydrating the patient and reduce the sickling process.

Objectives: To assess the analgesic efficacy and adverse events of pharmacological interventions to treat acute painful sickle cell vaso-occlusive crises in adults, in any setting.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, Embase via Ovid and LILACS, from inception to September 2019. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.

Selection criteria: Randomized, controlled, double-blind trials of pharmacological interventions, of any dose and by any route, compared to placebo or any active comparator, for the treatment (not prevention) of painful sickle cell VOC in adults.

Data collection and analysis: Three review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio (RR) and number needed to treat for one additional event, using standard methods. Our primary outcomes were participant-reported pain relief of 50%, or 30%, or greater; Patient Global Impression of Change (PGIC) very much improved, or much or very much improved. Our secondary outcomes included adverse events, serious adverse events, and withdrawals due to adverse events. We assessed GRADE and created three 'Summary of findings' tables.

Main results: We included nine studies with data for 638 VOC events and 594 participants aged 17 to 42 years with SCD presenting to a hospital emergency department in a painful VOC. Three studies investigated a non-steroidal anti-inflammatory drug (NSAID) compared to placebo. One study compared an opioid with a placebo, two studies compared an opioid with an active comparator, two studies compared an anticoagulant with a placebo, and one study compared a combination of three drugs with a combination of four drugs. Risk of bias across the nine studies varied. Studies were primarily at an unclear risk of selection, performance, and detection bias. Studies were primarily at a high risk of bias for size with fewer than 50 participants per treatment arm; two studies had 50 to 199 participants per treatment arm (unclear risk). Non-steroidal anti-inflammatory drugs (NSAID) compared with placebo No data were reported regarding participant-reported pain relief of 50% or 30% or greater. The efficacy was uncertain regarding PGIC very much improved, and PGIC much or very much improved (no difference; 1 study, 21 participants; very low-quality evidence). Very low-quality, uncertain results suggested similar rates of adverse events across both the NSAIDs group (16/45 adverse events, 1/56 serious adverse events, and 1/56 withdrawal due to adverse events) and the placebo group (19/45 adverse events, 2/56 serious adverse events, and 1/56 withdrawal due to adverse events). Opioids compared with placebo No data were reported regarding participant-reported pain relief of 50% or 30%, PGIC, or adverse events (any adverse event, serious adverse events, and withdrawals due to adverse events). Opioids compared with active comparator No data were reported regarding participant-reported pain relief of 50% or 30% or greater. The results were uncertain regarding PGIC very much improved (33% of the opioids group versus 19% of the placebo group). No data were reported regarding PGIC much or very much improved. Very low-quality, uncertain results suggested similar rates of adverse events across both the opioids group (9/66 adverse events, and 0/66 serious adverse events) and the placebo group (7/64 adverse events, 0/66 serious adverse events). No data were reported regarding withdrawal due to adverse events. Quality of the evidence We downgraded the quality of the evidence by three levels to very low-quality because there are too few data to have confidence in results (e.g. too few participants per treatment arm). Where no data were reported for an outcome, we had no evidence to support or refute (quality of the evidence is unknown).

Authors' conclusions: This review identified only nine studies, with insufficient data for all pharmacological interventions for analysis. The available evidence is very uncertain regarding the efficacy or harm from pharmacological interventions used to treat pain related to sickle cell VOC in adults. This area could benefit most from more high quality, certain evidence, as well as the establishment of suitable registries which record interventions and outcomes for this group of people.

PubMed Disclaimer

Conflict of interest statement

TC: none known.

IH: none known.

SB is an internist specializing in basic and clinical haematology with an emphasis on the management of adult and children with sickle cell disease and pain. SB has been in the Speakers Bureau of Novartis with an emphasis on Deferasirox (both Exjade and Jadenu formulations) in September 2016.

BJ: none known.

PW undertakes work for GSK under the auspices of his company Oxford Systematic Review Services. The work is related to over‐the‐counter analgesics.

The protocol for this review was identified in a 2019 audit as not meeting the current definition of the Cochrane Commercial Sponsorship policy. At the time of its publication it was compliant with the interpretation of the existing policy. A new author team fully compliant with the 2014 policy completed the review. As with all reviews, new and updated, at update this review will be revised according to 2020 policy update.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Non‐steroidal anti‐inflammatory drugs (NSAIDs) versus placebo, outcome: 1.1 Patient Global Impression of Change very much improved.
4
4
Forest plot of comparison: 1 Non‐steroidal anti‐inflammatory drugs (NSAIDs) versus placebo, outcome: 1.2 Patient Global Impression of Change much or very much improved.
1.1
1.1. Analysis
Comparison 1 Non‐steroidal anti‐inflammatory drugs (NSAIDs) versus placebo, Outcome 1 Patient Global Impression of Change very much improved.
1.2
1.2. Analysis
Comparison 1 Non‐steroidal anti‐inflammatory drugs (NSAIDs) versus placebo, Outcome 2 Patient Global Impression of Change much or very much improved.
1.3
1.3. Analysis
Comparison 1 Non‐steroidal anti‐inflammatory drugs (NSAIDs) versus placebo, Outcome 3 Opioid consumption.
1.4
1.4. Analysis
Comparison 1 Non‐steroidal anti‐inflammatory drugs (NSAIDs) versus placebo, Outcome 4 Time to pain resolution (hours).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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References to studies awaiting assessment

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References to ongoing studies

IRCT2016072511956N6 {published data only}
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NCT03431285 {published data only}
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NCT03978156 {published data only}
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