Pharmacological interventions for painful sickle cell vaso‐occlusive crises in adults Stable (no update expected for reasons given in 'What's new')

Abstract

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.

Author(s)

Tess E Cooper, Ian R Hambleton, Samir K Ballas, Brydee A Cashmore, Philip J Wiffen

Abstract

Plain language summary

Medicines for treating painful sickle cell crises in adults

Bottom line

We are uncertain which medicines provide the best pain relief for adults experiencing a painful sickle cell crisis.

Background

People with sickle cell disease have abnormally shaped red cells in their blood. Sickle cell disease is the most common inherited blood disorder around the world. It is estimated globally that 367 million to 500 million people are carriers. People with sickle cell disease have a higher chance of life‐threatening complications, such as infection, severe chest pain and stroke in early life, and kidney or liver damage in adulthood.

A pain crisis is the most common problem of sickle cell disease and can require several treatments at once, usually in an emergency situation. The first priority is to control the pain, using medicines (such as opioids, non‐steroidal anti‐inflammatories, paracetamol, and blood thinners) or relaxation, hypnosis, heat, ice, or acupuncture.

Study characteristics

In September 2019, we searched for clinical trials that used medicines in any setting to treat painful sickle cell crises. We found nine trials, with 594 adults (aged 17 to 42 years) who had sickle cell disease, experiencing a combined total of 638 painful episodes.

Key results

The studies looked at different comparisons of the medicines butorphanol, cetiedil, fentanyl, ketoprofen, ketorolac, metoclopramide, morphine, paracetamol, placebo, tinzaparin, and tramadol. Only three studies compared the same two drugs (non‐steroidal anti‐inflammatory drugs such as ibuprofen, aspirin, or naproxen, with a placebo (pretend treatment)) and we had very limited data to be able to investigate the effects on pain scores from these medicines.

Side effects were rare and were generally mild.

Quality of the evidence

We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results. For pain relief and side effects, we rated the quality of evidence as very low.

We downgraded the quality of the evidence to very low because there were not enough data (e.g. too few participants). For some outcomes the quality of the evidence is unknown because there was no evidence available.

Author(s)

Tess E Cooper, Ian R Hambleton, Samir K Ballas, Brydee A Cashmore, Philip J Wiffen

Reviewer's Conclusions

Authors' conclusions

Implications for practice For people with sickle cell disease

The amount and quality of evidence around the use of any pharmacological treatment for painful sickle cell vaso‐occlusive crises (VOC) is very low. This means treatment is based on clinical experience and advice from respected authorities. We could make no judgement about which pharmacological treatment is more effective than any other to reduce the painful crisis. We could make no judgement about adverse events or withdrawals.

Sickle cell pain should be treated by specialists in this area.

For clinicians

The amount and quality of evidence around the use of any pharmacological treatment for painful sickle cell VOC is very low. This means treatment is based on clinical experience and advice from respected authorities. We could make no judgement about which pharmacological treatment is more effective than any other to reduce the painful crisis. We could make no judgement about adverse events or withdrawals.

Clinicians who do not have expertise in this field should defer to clinicians with specialist knowledge.

For policy makers and funders of the intervention

The amount and quality of evidence around the use of any pharmacological treatment for painful sickle cell VOC is very low. This means treatment is based on clinical experience and advice from respected authorities. We could make no judgement about which pharmacological treatment is more effective than any other to reduce the painful crisis. We could make no judgement about adverse events or withdrawals.

Specialist services treating people with sickle cell disease will need to be supported (by clinical expertise and multi‐factorial service models) to provide adequate treatment.

Implications for research

The results of this review are disappointing with fewer than 600 participants included in relevant randomized controlled trials. While it would be easy to suggest more trials are needed, and they probably are, it may be that a different approach is necessary. One possible route is the establishment of suitable registries for this group of people which records interventions and outcomes. To achieve any progress, thought needs to be given to relevant outcomes for this patient group.

With the advent of precision medicine, the use of analgesics in general and opioids in particular should be based on recent advances in the pharmacodynamics and pharmacokinetics of opioids. Pharmacodynamically, opioids are ligands that bind and activate specific receptors that modulate the transmission of painful stimuli in the central nervous system. Accordingly, the analgesic potential of a specific opioid depends on the number of receptors and the ability of the opioid to bind to these receptors. Since these factors vary among people, so does the analgesic potential. In addition, pharmacokinetically, opioids are metabolized by specific enzymes into metabolites that could be analgesically active or inactive depending on the opioid being used. These enzymes could be duplicated, triplicated, mutated or deleted in different people thus causing significant variation in pain relief among patients. Hopefully, these pharmacological markers could be determined for each person in the future which allows the choice of the best opioid compatible with the person in question.

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