Integrative approaches to treating pain in sickle cell disease: pre-clinical and clinical evidence

Abstract

Sickle cell disease (SCD) is a genetic disorder characterized by hemolysis, end-organ damage, inflammation, and pain. Recurrent and unpredictable episodes of acute pain due to vaso-occlusive crises are a unique feature of SCD. Many patients also develop lifelong chronic pain. Opioids are the primary method of pain treatment in SCD; however, continued use is associated with several adverse effects. Integrative approaches to treating pain in SCD are increasingly being explored to prevent the side effects associated with opioids. In this review, we highlight the mechanisms of pain in SCD and describe mechanism-based integrative approaches for treating pain.

Introduction:

Sickle cell disease (SCD) is an autosomal recessive disorder caused by a point mutation in the β-globin gene of hemoglobin.¹ It is characterized by recurrent vaso-occlusive crises (VOCs) in which interactions between red blood cells (RBCs) carrying sickle hemoglobin and the endothelium lead to microvascular obstruction with impaired blood and oxygen supply to the periphery. Episodes of VOC manifest clinically as recurrent and unpredictable episodes of acute pain.^2,3 SCD is also associated with comorbidities including chronic pain, organ damage, and stroke.⁴ The pathobiology of SCD involves severe inflammation, oxidative stress, and endothelial dysfunction which may contribute to a noxious microenvironment leading to pain.^1–8 The mainstay of pain therapy in SCD is opioids which have several side effects including nausea, constipation, and pruritus.^9,10 Complementary and integrative approaches to treating pain are increasingly being explored to avoid the complications of long-term opioid use. Here, we describe the current mechanistic understanding of pain in SCD and highlight evidence-based integrative approaches to treating pain.

Pain in SCD:

Pain remains a major consequence of SCD.² Patients with SCD experience pain either as acute episodes and/or as ongoing chronic pain.^2,11 The pathobiology of pain in SCD involves nociceptive, neuropathic, and inflammatory mechanisms (Figure 1).² Mechanisms of pain remain to be established but recent progress made using mouse models suggests both peripheral and central nervous system involvement.^10,12

Figure 1|. Mechanisms of pain transmission and perception in sickle cell disease.

Mechanisms of nociception are complex involving contributions from the peripheral and central nervous system. (1) An action potential is generated from a peripheral nociceptor and the signal is transmitted via the primary afferent through the dorsal horn and first-order neurons in the DRG. (2) This signal can be modulated (activated or inhibited) in the spinal cord after activation of second order neurons via interneurons and/or descending projections from the brainstem involving neurotransmitters such as serotonin. (3) The final signal that is transmitted to the higher brain centers is then translated by the brain into the subjective perception of pain.

Mouse Models of Pain in SCD

Transgenic HbSS-BERK and HbSS-Townes mice express exclusively human sickle hemoglobin and display characteristic features of pain similar to patients with SCD.^11,13–21 Acute pain has also been evoked in these mice via hypoxia/reoxygenation (H/R) treatment to simulate VOC.¹⁴ Furthermore, the neurochemical signatures of pain in these mice parallel those observed in patients with SCD.^{17,18,22–25} These mice have provided critical insights into the mechanisms of pain in SCD, and much of the current evidence arises from studies using these mice.

Acute Pain

Episodes of acute pain are evoked by VOC during which sickle RBCs adhere to the activated endothelium leading to vaso-occlusion of blood vessels.^2,26,27 Adherence to the endothelium involves complex interactions between sickle RBCs, leukocytes, platelets, and endothelial adhesion molecules such as E- and P-selectin.^28–32 Occlusion of vessels is accompanied by ischemia-reperfusion injury, inflammation, hemolysis, and oxidative stress.^2,26,27 It remains to be known how vasoocclusion causes pain.

Central Sensitization and Chronic Pain

The precise etiology of chronic pain in SCD remains unclear as it can arise from a state of sensory hyperexcitability following noxious stimuli. SCD is known to have a heightened systemic inflammatory state exhibiting high levels of several pro-inflammatory cytokines including interleukin [IL]-1α, IL-1β, IL-6, monocyte chemoattractant protein [MCP]-1, and tumor necrosis factor [TNF]-α.^33–36 In addition to systemic inflammation, SCD is also characterized by localized immune cell mediated neuroinflammation in the central and peripheral nervous system with contributions from mast cells, leukocytes, and glial cells.^{10,12,22,23,37,38} We have shown that mast cell degranulation leads to the release of neuropeptide substance P (SP) from peripheral nerve terminals in sickle mice.²³ SP stimulates arterial dilation and vascular permeability contributing to neurogenic inflammation and in turn activates mast cells leading to a vicious cycle of mast cell degranulation, neurogenic inflammation, and pain. Opioids have been known to activate mast cells. Therefore, on one hand, opioids may act as an analgesic via their action on the nervous system while also stimulating pain by activating mast cells.

Furthermore, we have found elevated levels of oxidative stress, substance P (SP), and glial fibrillary acidic protein (GFAP) in the dorsal horn of sickle mice when compared to control mice.²² Thus, constitutive activation of peripheral nociceptors and second order-neurons in the spinal cord due to persistent inflammation leads to sustained transmission of action potentials. We found that nociceptors in spinal dorsal horn neurons are constitutively hyperactivated in sickle mice, suggestive of central sensitization.³⁹ Neuroimaging of the brain in patients with SCD also suggests central sensitization.⁴⁰ Additionally, peripheral nociceptor sensitization was observed by us in sickle mice.⁴¹ Hypersensitivity to noxious and innocuous stimuli, referred to as “hyperalgesia” and “allodynia”, respectively has also been observed in both sickle mice and patients with SCD.^{13–18,20,23,42} Continued excitation of peripheral nociceptors may progress to hyperexcitability of central neurons, which is known as central sensitization.^10,15,39,40 This central sensitization or hyperexcitability may underlie chronic pain and poor response to analgesic therapy.

Neuromodulatory influences on pain

The spinal dorsal horn serves as the gate of convergence for signals from the periphery and the higher brain regions.⁴³ A complex interplay between impulses from peripheral neurons, modulation from descending neuronal fibers, and excitatory and inhibitory neurotransmitters and interneurons determines perception of pain.⁴³ Signals in the dorsal horn are modulated by neurotransmitters such as serotonin and dopamine, as well as endogenous opioids, glycine, and others.⁴³ Top-down mechanisms may be influenced by perception and thus can result in affective modulation of pain. The precise nature of pain perception depends on the processing of modulated signals in different brain areas such as the somatosensory cortex, prefrontal cortex, and the amygdala.⁴³ These mechanisms may be extremely important in SCD to modulate existing central sensitization by releasing inhibitory neurotransmitters from higher brain centers into the dorsal horn of the spinal cord to modify pain pathways leading to inhibition of transmission of pain signals from the spinal cord dorsal horn to the brain. Modulation of top-down mechanisms with integrative approaches may reduce pain and reduce analgesic use.

Integrative approaches to treating pain:

Complementary and integrative medicine including dietary supplements, acupuncture, and perception-based therapies are increasingly being explored in pre-clinical and clinical trials for treating pain in SCD (Table 1).

Table 1 |.

Integrative and complementary therapies to treat pain in sickle cell disease

Treatment	Studied Outcomes
Anti-inflammatory and antioxidant
Curcumin and CoQ10	Decreased glial activation, neuroinflammation, and oxidative stress in spinal cords of sickle mice, leading to amelioration of hyperalgesia; reduced inflammation, oxidative stress, and VOC evoked pain in patients with SCD
L-glutamine	Reduction in frequency of pain crises in adult and pediatric patients with SCD
Dietary supplements
High protein mouse diet	Reduced ischemic end-organ damage, increased muscle mass, bone density, and grip strength while decreasing vascular leakage in sickle mice
Zinc	Promoted growth and decreased incidence of infection in pediatric patients with SCD
Omega-3 fatty acids	Reduced opioid analgesic use and pain related school absences in pediatric sickle patients
Arginine	Decreased hemolysis and oxidative stress in sickle mice; alleviated VOC evoked pain and decreased opioid use in patients with SCD
Mouse sickle diet	Improved survival and decreased hyperalgesia by increasing serotonergic descending modulation in sickle mice
Acupuncture
Electroacupuncture	Reduced inflammatory cytokines, SP, and neurogenic inflammation leading to decreased hyperalgesia in sickle mice; effective in reducing pain in patients with SCD
Perception based
Hypnosis	Decreased pain intensity and improved pain tolerance and threshold in patients with SCD
Virtual Reality	Reduced median VOC pain intensity, number of body areas, and temporal pain domains in patients with SCD.

Antioxidant and Anti-Inflammatory Therapies

We found that curcumin, a component of turmeric, and coenzyme Q10 (CoQ10) independently and in conjunction reduce microglial activation, SP, and reactive oxygen species (ROS) in the spinal cords of sickle mice.²² These findings were accompanied by attenuation of chronic hyperalgesia in sickle mice.²² In a clinical study of patients with SCD, treatment with CoQ10 reduced inflammation, oxidative stress, and the incidence of VOC.⁴⁴ Theracurcumin, a modified form of curcumin with higher bioavailability, has been shown to be effective in reducing pain, inflammation, and oxidative stress in osteoarthritis.^45,46 Furthermore, curcumin reduced oxidative stress in thalassemia patients, which is a common co-existing condition with SCD.⁴⁷ Thus, curcumin and CoQ10 may serve as relatively non-toxic complementary therapies for treating sickle pathobiology.

Supplementation with L-glutamine has also been shown to have beneficial effects in reducing oxidative stress and endothelial adhesion of RBCs in SCD.^48,49 A clinical trial for L-glutamine showed significant reduction in the number of pain crises in both adult and pediatric patients with SCD.⁵⁰ Following these findings, L-glutamine was approved by the FDA for reducing VOC in SCD.

Dietary Supplementation

Deficiencies in many nutrients including vitamins, zinc, and fatty acids are common in SCD.⁵¹ Supplementation with nutrients has been shown to influence the pathobiology of SCD in mouse models and in some cases improve clinical outcomes. Maintenance on a high-protein mouse diet reduced ischemic end-organ damage, increased muscle mass, bone density, and grip strength while decreasing vascular leakage in sickle mice.^52,53 Zinc supplementation improved growth and decreased incidence of infections in pediatric sickle cell patients.⁵⁴ Omega-3-fatty acid supplementation resulted in a significant reduction in sickle cell pain related school absences and opioid analgesic use, as well as a non-statistically significant 45% reduction in the rate of sickle cell crises in pediatric sickle patients.⁵⁵ Arginine supplementation enhanced nitric oxide bioavailability, and decreased both hemolysis and oxidative stress in sickle mice.⁵⁶ Furthermore, arginine supplementation has been shown to alleviate VOC evoked pain and decrease opioid use in a single center clinical trial.⁵⁷ In addition to individual nutritional supplements, an enriched mouse sickle diet combining increased protein, amino acids, fatty acids and other micronutrients was shown to significantly improve survival in sickle mice when compared to those fed a regular diet.⁵⁸ We also found that the mouse sickle diet was able to significantly attenuate chronic hyperalgesia in sickle mice by increasing descending modulation via serotonin (Manuscript under revision). These findings suggest that dietary interventions may be effective in improving pain and survival in SCD, but further pre-clinical and clinical trials are required.

Acupuncture

We previously found that electroacupuncture (EA) in awake sickle mice was able to alter the inflammatory sickle microenvironment and influence nociception.⁵⁹ EA treatment led to a reduction in inflammatory cytokines, SP, and neurogenic inflammation in both the periphery and spinal cords of sickle mice.⁵⁹ The antinociceptive effect, however, varied between sickle mice with a range of responses from high to moderate to no response.⁵⁹ Sickle mice that showed moderate to no response to EA treatment uniformly exhibited high levels of SP and phospho-p38 mitogen-activated protein kinase (MAPK) in the spinal cord.⁶⁰ Combined treatment in these mice with EA and either Netupitant, an inhibitor of the SP receptor neurokinin 1 (NK1R), or SB203580, a p38 MAPK inhibitor, led to a significant decrease in chronic hyperalgesia that was not observed with either treatment alone.⁶⁰ In addition, a retrospective review of sickle patients treated at the National Institutes of Health found that both inpatient and outpatient acupuncture treatment for VOC was effective in reducing pain.⁶¹ These findings suggest that a combination of integrative approaches such as curcumin, to reduce spinal SP, in conjunction with EA may be a useful therapeutic strategy for treating pain in SCD following appropriate clinical investigation.

Perception Based and Mind-Body Therapies

Perception of pain is a subjective experience driven by somatosensory nociceptive activity and modulation from cognitive and emotional higher brain centers. Activation of the descending neuromodulatory pathway via non-pharmacological interventions is a potential approach to reduce pain. Mindfulness, relaxation, hypnosis, and cognitive behavioral therapy have all been effective in alleviating chronic pain.^62,63 A single 30-minute hypnosis session was shown to decrease pain intensity and improve pain threshold and tolerance in patients with SCD.⁶² Immersive virtual reality also showed an improvement in VOC pain experience in patients with SCD.⁶⁴ Additionally, a randomized controlled trial of yoga in pediatric sickle cell patients hospitalized for VOC found that those who completed a single 30 minute guided yoga session had a greater reduction in mean pain level when compared to the control group.⁶⁵ Thus, incorporating perception-based and mind-body therapies may be supportive of decreasing both chronic and acute pain in SCD.

Future Perspectives:

Therapies that target the underlying pathobiology of SCD are urgently needed to avoid the reliance on opioids for treating pain in SCD. Several integrative strategies targeting peripheral, central, and descending neuromodulatory mechanisms of pain are currently under development and show promising pre-clinical results. Since pain is driven by perception in addition to the pathophysiology causing pain, it can be modulated by perception-based approaches devoid of use of additional medications. Many comorbidities may lead to usage of multiple drugs which may cause toxicities and side-effects. Therefore, perception-based strategies need to be examined for treating pain in SCD. Clinical trials are needed to further evaluate the efficacy of these interventions for treating pain in SCD.

Highlights.

• Pain is a major comorbidity of sickle cell disease with many patients suffering from both acute and chronic pain

• Mechanisms of pain manifestation in sickle cell disease are complex and include contributions from both the central and peripheral nervous systems

• Integrative approaches for treating pain in sickle cell disease are being explored in several pre-clinical and clinical studies