Sickle Cell Disease Management of Acute and Chronic Pain

Remarks:

• NSAIDs herein are defined broadly to include selective and nonselective cyclooxygenase (COX) inhibitors.

• Patient-specific assessment of harms, including but not limited to renal, vascular, and gastrointestinal toxicity, anticoagulation requirements, and cardiovascular disease, will help identify patients who are appropriate for NSAID therapy and tailor the selection of the drug/class of NSAID based on this risk profile.

• Patients specifically at increased risk of renal toxicity need to be identified. If comorbidities (eg, peptic ulcer disease, renal dysfunction, full-dose anticoagulation) are a significant risk factor, the mild potential benefit may not outweigh the risk.

Remarks:

• Steroids should still be used when appropriate for the treatment of other medical indications such as asthma.

• Systemic corticosteroid exposure, particularly cessation of steroids, has been associated with rebound pain and other complications; therefore, the decision to use steroids for other medical indications should be made in collaboration with experts in SCD.

Remarks:

• This recommendation assumes safe administration of subanesthetic ketamine infusions in the hospital inpatient unit in centers that have appropriate expertise to administer the drug.

• Recommended dose for subanesthetic (analgesic) infusion for acute exacerbation of SCD pain starts at 0.1 to 0.3 mg/kg per hour with a maximum of 1 mg/kg per hour.

• Currently, there is no standardized, widely accepted definition for the word refractory; therefore, whether pain is considered refractory is determined at the clinician’s discretion.

Remarks:

• Regional anesthesia in this context is defined as epidural or peripheral nerve catheter-delivered analgesia for abdominal, hip, or leg pain.

• The procedure needs to be technically feasible based on the anatomical location of the pain.

• A thorough explanation of the procedure as well as risks, benefits, and alternative options should be provided to patients and families before the procedure.

• The recommendation assumes administration of the procedure in a center that has appropriate resources and expertise.

• There is considerable uncertainty around optimal timing and indications for regional anesthesia interventions; however, the panel emphasized the importance of shared decision making based on the patient’s knowledge of his or her own disease and course of pain-related complications and strategies that promote reduced opioid requirements, improved function, pain management, and reduced duration of hospitalization.

Remarks:

• The panel acknowledges that the risk of harm with IV fluids may be greater in adults than children because of deficiencies in cardiopulmonary function and other comorbid conditions.

• This nonrecommendation includes bolus infusions and infusions to maintain fluid balance requirements in addition to the types of fluids (eg, normal [0.9%] saline vs half-normal [0.45%] saline) that are used in these infusions.

• This nonrecommendation does not preclude the administration of fluids to patients with clinically significant dehydration.

Remarks:

• This recommendation is based on direct evidence from patients with SCD and indirect evidence largely from postoperative adult mixed surgical populations.

• Despite the evidence being primarily based on adult populations, there is low risk of harm in children. However, a tailored approach should be used that matches feasibility and acceptability for a given patient. Some interventions may not apply to younger children; therefore, the age of the patient should be considered, especially for interventions such as yoga and guided AV relaxation.

• Time requirements, financial costs, availability, and training of therapists for these types of treatments are important factors in treatment selection and should be discussed with patients in the course of shared decision making.

Remarks:

• If biofeedback and acupuncture are considered, a tailored approach is necessary that matches feasibility, acceptability, and patient experience and preference regarding these interventions for a given patient.

• Discussion with patients in the course of shared decision making needs to include important factors such as the time, financial costs, availability, and training of the therapists required to perform these treatments.

Remarks:

• This recommendation assumes that these hospital-based facilities have readily available code team coverage to ensure delivery of the safest care.

• From a hospital or system perspective, more detailed cost analyses would be warranted before deciding on implementation for a given institution. SCD-specific hospital-based acute care facilities tend to be cost effective to the extent that they reduce ED visits and admissions; however, overall acute care utilization may increase.

• Most of the evidence describing hospital-based acute care facilities places pain treatment in the context of complex SCD comprehensive care models. In these models, >1 intervention is likely driving the improvement and continuity in care.

Remarks: For clarity, the panel defined the specific terms used as follows:

• Basal: continuous IV opioid infusion.

• On-demand dosing: opioid administered at an interval that relies on patients declaring their own need. Opioid can be administered via a patient-controlled IV analgesia pump or via an as-needed order for intermittent nurse-administered drug.

• Scheduled intermittent dosing: opioid administered on a timed schedule that does not rely on the patient asking for the drug.

Remarks:

• NSAIDs herein are defined broadly to include selective and nonselective COX inhibitors.

• There was a lack of both direct and indirect evidence for all-cause avascular necrosis nonsurgical pain management. Therefore, the panel chose to use osteoarthritis as an indirect evidence source, because it is a degenerative arthropathy with a reasonable evidence base. This evidence base is restricted to adults.

• Surgical and nonsurgical approaches to the treatment of the underlying cause of avascular necrosis were not the focus of this recommendation.

Remarks:

• This recommendation is based largely on indirect evidence from adult patients without SCD affected with fibromyalgia. Fibromyalgia was selected by panel consensus as the entity most closely aligned with chronic pain in SCD (with no identifiable cause beyond SCD).

• Antidepressants may increase the risk of suicidal ideation and behavior in children and adolescents with major depression disorder and other psychiatric disorders.

• The significant lack of pediatric data for the use of SNRIs for pain management could not support a recommendation for this age group.

Remarks:

• This recommendation is based largely on indirect evidence from adult patients without SCD affected with fibromyalgia. Fibromyalgia was selected by panel consensus as the entity most closely aligned with chronic pain in SCD with no identifiable cause.

• Antidepressants may increase the risk of suicidal ideation and behavior in children and adolescents with major depression disorder and other psychiatric disorders.

• The significant lack of pediatric data for the use of TCAs for pain management could not support a recommendation for this age group.

• The increased adverse effect profile for this drug includes, but is not limited to, prolonged QT, orthostasis, cognitive impairment, dry mouth, and anticholinergic effects. These adverse effects should be considered and discussed with patients.

Remarks:

• This recommendation is based largely on indirect evidence from adult patients without SCD affected with fibromyalgia. Fibromyalgia was selected by panel consensus as the entity most closely aligned with chronic pain in SCD with no identifiable cause.

• The significant lack of pediatric data for the use of gabapentinoids for pain management could not support a recommendation for this age group.

Remarks:

• The cognitive or behavioral pain management strategy with the broadest evidence base is cognitive behavioral therapy (CBT). Other strategies considered by the panel with lower certainty in evidence include acceptance and commitment therapy (ACT), mindfulness-based treatments, coping skills training, and operant therapy.

• This recommendation is based mainly on indirect evidence. The treatments that have been tested in SCD are in children with acute pain without establishing the presence of chronic pain or the intervention’s effects on chronic pain. The outcomes assessed in SCD have not typically included pain intensity. The greater body of indirect evidence was drawn from the literature in individuals with fibromyalgia and nonspecific lower back pain.

• No standardized, manualized universally accepted version of CBT is available for SCD in either adults or children. This is a significant clinical and translational research need. Nonetheless, such strategies have shown broad applicability in pediatric and adult chronic noncancer pain.

• Interventions based on CBT, coping skills training, and guided imagery have some evidence base for SCD, although mainly in children and for episodic pain.

• In other conditions, these methods are believed to have low risks and are portable in that patients can use the skills learned on their own after treatment, possibly with intermittent booster sessions.

• Time, financial costs, availability, and training of therapists (ie, in chronic pain and SCD) and patient burden can be barriers to these types of psychological treatments that are being recommended.

• Cognitive and behavioral pain management strategies should be used in conjunction with other modalities as part of a comprehensive and multimodal pain management plan.

• Behavioral and cognitive strategies are optimal in a setting where the patient is motivated and there is access to appropriately trained personnel.

Remarks:

• Time, financial costs, availability, and training of therapists (ie, chronic pain and SCD) and patient burden can be barriers to these types of treatments.

• There is currently a lack of evidence in children; however, some pediatric patients may be using these treatments at home.

Remarks:

• Optimization of SCD management is a priority.

• In those whose pain has been refractory to multiple other interventions, COT should be considered after risk stratification using a validated tool, based on how well patients’ SCD is managed, comprehensive assessment of behavioral risks (eg, risk factors for opioid misuse), implications of tolerance on the management of acute pain episodes, and other known adverse effects of opioids. Adverse events noted in other non-SCD patient populations are dose dependent and include increased risk of poor surgical outcomes, increased risk of motor vehicle collisions, myocardial infarction, bone fracture, and mortality. Patients on doses of >120 mg of morphine milligram equivalents (MME) are at risk for hormonal alterations, which can lead to sexual dysfunction. Doses >100 mg of MME are associated with a ninefold increase in risk of overdose compared with doses <20 mg of MME in general non-SCD pain populations.

• Failure criteria for a trial of COT should be discussed in the shared decision-making process, and alternative treatments in the case of failure and a plan for opioid cessation should be developed before initiation. Documentation of this discussion and the goals of care should be included in the medical record.

• The lowest effective opioid dose should be prescribed.

• Patients on COT should avoid the use of benzodiazepines, sedating medications, and alcohol.

• Providers should be aware that patients may inadvertently end up on COT if episodic pain is frequent enough that patients are receiving frequent opioid treatment of recurrent pain. Therefore, providers should make efforts to reduce or eliminate scheduled opioid doses between acute episodic pain events, which may reduce the likelihood of unintentional COT.

Remarks:

• Optimization of SCD management is a priority.

• The benefit of COT in SCD is largely unknown, and the harms are established via indirect evidence (recommendation 9a, remark 2); therefore, shared decision making is essential and may lead to continuation once risks of COT and tapering are explained.

• Function should be assessed from the shared patient/clinician perspective. The use of standardized patient-reported outcome tools that assess patient functioning is encouraged.

• COT is discussed as a class of drugs. Individual opioid drugs have different specific toxicity profiles and interactions with end-organ injury. Therefore, a review of the individual profile of each drug under consideration for use should be performed for a given patient.

• The lowest effective opioid dose should be prescribed.

• Patients on COT should avoid the use of benzodiazepines, sedating medications, and alcohol.

• Patients on COT require careful monitoring with regard to functional status and risk assessment for the development of aberrant opioid use and medical, social, behavioral, or psychological complications as a precursor to opioid dose reduction or weaning.

• The risk of adverse events related to COT rises as the total dose increases. Therefore, patients on high doses of opioids need close monitoring for complications and adverse effects.

Remarks:

• Optimization of SCD management is a priority.

• Collaboration with a pain specialist should be strongly considered for additional or alternative pain management strategies.

• Weaning and/or withdrawal from COT is potentially a higher-risk entity in patients with SCD (ie, risk of triggering vasoocclusive events or other medical complications) and should be done carefully.

• The other recommendations provided in this summary should be used for potential alternatives that could be part of a comprehensive pain management plan.

• Patients on COT should avoid the use of benzodiazepines, sedating medications, and alcohol.

• Acute pain events may still be treated with opioid analgesia if this serves the overall pain treatment plan, but this should be done in conjunction with the primary outpatient management team. Furthermore, nonopioid medications and integrative therapies should also be offered as outlined in prior recommendations.

Remarks:

• In unique circumstances when all other measures to control recurrent pain episodes have failed (eg, hydroxyurea, other disease modifying therapies) and when shared decision making can be fully applied, a trial of monthly transfusions may be reasonable.

• The decision should be influenced primarily by patient preference where patients appreciate the uncertainty in benefit over the burden and risks of monthly transfusion. Integration of education and informed shared decision making around initiation and/or cessation of chronic transfusion therapy is important.

• IV access and adherence to chelation and erythrocytopheresis are also considerations that could favor monthly transfusions in the exceptional circumstances noted above.

• The cessation of chronic transfusions can be associated with other SCD complications. Therefore, it is important to exercise caution if cessation of chronic transfusion is considered, including initiation of other disease-modifying therapies and increased surveillance.