Review highlights non-opioid options for sickle cell pain management
Combined with standard opioid care, they may provide meaningful relief
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Common pain relievers, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, combined with standard opioid care, may provide meaningful relief for acute pain in people with sickle cell disease (SCD), according to a review study.
Cognitive behavioral therapy, a type of talk therapy, also showed signs of efficacy against chronic SCD pain, while other treatments, including ketamine and lidocaine, “represent promising adjunctive anesthetic-based therapies for sickle cell related pain,” researchers wrote.
“Overall, the literature suggests that several modalities may provide meaningful improvements in pain scores and contribute to more personalized multimodal [multiple intervention] regimens for SCD patients,” they added.
The review study, “Evaluation of non-opioid therapies for pain management of sickle cell disease: a literature-based review,” was published in the Annals of Hematology.
Many sickle cell patients also develop chronic, ongoing pain
SCD is an inherited disorder in which red blood cells become rigid and crescent-shaped. This causes cells to stick to blood vessel walls and block blood flow, leading to episodes of severe pain called vaso-occlusive crises (VOCs).
Beyond these acute episodes, many patients also develop chronic, ongoing pain, which can involve nerve damage (neuropathic pain) and a condition called central sensitization, where the nervous system becomes more sensitive to pain signals over time.
Opioids are a class of therapies used for managing moderate to severe pain in SCD. However, they come with limitations in terms of side effects, tolerance, dependence, and stigma that patients may face when seeking pain treatment.
To identify non-opioid treatments that could be used alongside or instead of opioids, a trio of researchers in the U.S. systematically reviewed studies about this subject that were published between January 2009 to June 2026.
NSAIDS shown to reduce opioid use in some cases
More than 20 studies, including clinical trials, observational studies, and treatment guidelines, were included in the analysis. Data showed that NSAIDs, which reduce pain and inflammation, “are an integral component of non-opioid adjunct therapy in multimodal analgesic protocols,” the team wrote.
While NSAIDs can be taken via several routes, intravenous (into-the-vein) administration results in the fastest and most reliable effects for moderate to severe pain alongside opioids in VOCs. In some cases, they have been shown to reduce opioid use.
Still, NSAIDs use is limited mostly by their side effects, including gastrointestinal and kidney problems, bleeding abnormalities, and uncontrolled high blood pressure.
The current 2020 guidelines from the American Society of Hematology (ASH) suggest a five- to seven-day course of NSAIDs added to opioids during a crisis, but they also emphasize that more research is needed on long-term safety.
Acetaminophen showed strong evidence against SCD pain
Acetaminophen, also called paracetamol, showed strong evidence against SCD pain. Its advantages include high availability, low cost, ease of dosing, and minimal gastrointestinal and kidney-related side effects.
An appropriately controlled clinical trial of 104 children experiencing VOCs showed that intravenous acetaminophen provided better pain relief than intravenous diclofenac (an NSAID), while also reducing hospital stay length and opioid use.
Guidelines recommend the use of acetaminophen combined with other medications for acute and chronic pain management in SCD. Still, caution is required in those with liver disease and who drink alcohol regularly.
Two anesthetics, low-dose ketamine and lidocaine, have been used as an add-on IV therapy for hospitalized patients with severe pain who don’t respond to opioids. Small studies have shown that these therapies are associated with reductions in pain scores and opioid requirements when “incorporated into multimodal analgesic regimens,” the researchers wrote.
However, both carry several contraindications, and ASH guidelines don’t recommend ketamine as routine first-line treatment for acute VOCs and don’t include specific recommendations on lidocaine use.
Across the literature available at the time of this review, the strongest evidence for non-opioid pain management in SCD is supportive of the use of NSAIDs and [acetaminophen] for acute pain and CBT for chronic pain.
While guidelines suggest the use of antidepressants for adults with SCD, the review flags several safety considerations, including worsening opioid-related side effects and blood-related side effects that haven’t been studied specifically in SCD.
“Limited evidence suggests antidepressants may improve chronic pain symptoms, reduce opioid reliance, alleviate neuropathic pain, and help address psychosocial complications associated with SCD,” the team wrote.
Corticosteroids, powerful anti-inflammatory drugs, were found to potentially increase the risk of hospital readmission, and ASH guidelines do not recommend them for acute VOC pain.
Gabapentinoids (such as gabapentin) have been suggested as a therapeutic option for SCD-related chronic pain. Still, most of the supporting evidence is borrowed from research on other chronic pain conditions.
Cognitive behavioral therapy (CBT), which helps patients change how they think about and respond to pain, showed encouraging results across both pediatric and adult SCD patients. Still, “continued robust [appropriately-controlled clinical trials] are still needed to further define the long-term efficacy and implementation of CBT within guideline-level recommendations,” the researchers wrote.
While acupuncture, physical therapy, massage, and treatment with mild electrical currents were also mentioned as potentially helpful to manage day-to-day pain in SCD patients, current guidelines do not make recommendations on these approaches due to small sample sizes and limited appropriately controlled studies.
“Across the literature available at the time of this review, the strongest evidence for non-opioid pain management in SCD is supportive of the use of NSAIDs and [acetaminophen] for acute pain and CBT for chronic pain,” the researchers wrote. “A multimodal approach rather than opioid replacement alone represents the most promising pathway to improving pain outcomes in SCD.”
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