Evolution of Chronic Pain in Sickle Cell Disease

Abstract

Vaso-occlusive episodes (VOE), are the most common cause of health care encounters and are considered to be a hallmark of sickle cell disease (SCD). It has been increasingly recognized that many SCD patients, especially adults experience daily chronic pain (PiSCES study). While adolescents and young adults experience mostly acute episodic nociceptive pain, a significant number of adults develop chronic neuropathic and centralized pain. Although the precise mechanisms underlying this age-related transition in pain phenotype are not clearly understood, some factors that contribute to this phenomenon include chronic inflammation, organ damage and opioid induced hyperalgesia. Vincent et al (Blood, 2013) showed that mast cell activation is an important contributor to neurogenic inflammation and chronic pain in a mouse model of SCD. In an observational translational study, we recently reported that SCD patients with chronic pain (those who report pain >50% of time) were older and had higher levels of mast cell activation markers, plasma tryptase and substance P, compared to SCD patients who did not have chronic pain (Kuei et al, Blood, 2015). We report here the results of a prospective study of SCD patients (SS and Sβ0 thal) in different age groups. We tested the hypotheses that i) evolution to chronic pain is an age-dependent phenomenon, with higher frequency in older subjects, and ii) serum tryptase and substance P levels can be used as markers of chronic pain. A total of 36 subjects with SCD from the patient population of Pediatric and Adult sickle cell clinics of the MCG Sickle Cell Center were enrolled; these included 6 subjects aged 15-19, and 10 adults each in the age groups of 20-29, 30-39, and ≥40, respectively. Informed consent was obtained. Information on the frequency of VOEs (hospitalizations and ED visits) in the last 2 years, presence of chronic pain, hydroxyurea (HU) exposure, opioid usage as morphine equivalents within the past year, CBC, retics, CMP and % Hb F were collected. Quantitative sensory testing (QST) was performed using three different modalities: pressure pain sensitivity using a hand held computerized algometer AlgoMed, Medoc, Israel); heat and cold sensitivity (Q-Sense, Medoc, Israel); and Von Frey monofilament for neuropathic pain. Plasma tryptase and substance P levels were assayed by ELISA using kits from Biomatik inc, and Enzo Life Sciences, respectively. The results (lab tests, QST, VOEs, HU usage, plasma tryptase and substance P levels) are summarized in Table 1. Overall, there was an age dependent increase in the frequency of subjects with chronic pain; while 16.7% of patients in the 15-19 age group experienced chronic pain, this increased to 60.0% in the 20-29 year olds, and to 63.6% in those 30-39 years of age as shown in Figure 1. Among patients ≥40 years, 40.0% reported experiencing chronic pain. VOE frequency (average of last 2 years) was highest in the 20-29 age group (11.0/year) followed by 5.6 in the 30-39 age group. It was 2.57/year among 15-19 year olds, and 2.70/year in patients ≥40 years (p=0.004). Although Hb F and MCV was highest among ≥40 group (20.4%, and 112.1 fl, respectively), this did not reach statistical significance. As seen in the Table, BUN and creatinine showed a significant age dependent increase indicative of progressive organ damage. There was no significant difference between different age groups in other laboratory parameters, QST results, and plasma tryptase and substance P levels. The significant finding of this study is the higher frequency of VOEs in the 20-39 age group, compared to adolescents and patients 40 years and above. Although this finding is paralleled by a trend in opioid use, and frequency of chronic pain, these did not reach statistical significance in this relatively small group. The other interesting observation is the relatively mild course of disease in those ≥40 years of age (lower frequency of chronic pain, lower opioid use, lower VOE frequency). This seemingly paradoxical finding can be explained either by a survival advantage of the relatively mild patients, or a better adherence to HU, as suggested by higher MCV and Hb F in this group. The transition from adolescence to young adulthood is associated with a higher morbidity in SCD. Factors contributing to this phenomenon should be studied in a larger cohort. Disclosures Kutlar: Novartis Pharmaceuticals: Research Funding.

Vaso-occlusive crisis in sickle cell disease: current paradigm on pain management

“…The second form of sickle cell pain – the chronic pain syndromes – is associated with avascular necrosis of the femoral head, neuropathic pain, or pain related to persistent low-grade inflammation involving the chest, back, upper and lower extremities, and rarely leg ulcers. But sometimes, some patients who are older and have a history of extremely painful episodes are likely to evolve into a “chronic pain state” as previously reported12; these early signs of disturbed processing of pain may help clinicians who aim to circumvent disease progression 27. Finally, the third form (neuropathic pain) is poorly evaluated in SCD patients but has been demonstrated in transgenic murine models with SCD.…”

“…Although the pain of vaso-occlusive episodes is nociceptive, neuropathic pain has also been demonstrated in SCD patients aged 7 years and above by using quantitative sensory testing (QST) 11. In addition, age-dependent increase in the frequency of SCD patients with chronic pain has been reported, a phenomenon attributed to chronic inflammation, organ damage, and opioid-induced hyperalgesia 12. Thus, despite the use of opioids as the main analgesic therapy, other adjunct pharmacologic agents such as low-dose ketamine (a modulator of opioid tolerance and opioid-induced hyperalgesia) have been recommended for clinical use 13,14.…”

“…However, chronic pain is now a recognized form of pain, especially in adult SCD patients. Interestingly, it has been reported that older SCD patients with chronic pain have higher levels of mast-cell activation markers (serum tryptase and substance P) 12. Following degranulation of mast cells, tryptase is released into plasma and can result in inflammation, anaphylaxis, urticaria, and more importantly, neuropathic pain 21.…”

Pain Management for the Sickle Cell Patient

“…Although the exact mechanism underlying the transition from acute to chronic pain is not fully understood, some contributing factors include chronic inflammation, organ damage, and opioid-induced hyperalgesia [47]. According to a study presented at the Annual Meeting of American Society of Hematology, patients with chronic pain (defined as >50% of days reported as painful crises collected over 6 months) tend to be older (41 vs. 32 years), use more opioids (11.45 mg/day vs. 2.92 mg/day), and have higher levels of mast cell activation [48].…”

Blocking COX-2 for sickle cell pain relief

“…Chronic pain is reported in pediatric SCD patients, but the prevalence of this condition increases with age. 8 Would chronic R-flurbiprofen treatment prevent or delay the development of chronic SCD pain? Or would NSAID-related tissue toxicities outweigh the analgesic benefits of these drugs?…”