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New Look at Sickle Cell Patients With Chronic Pain

January 6, 2016
Many sickle cell disease (SCD) patients who have chronic pain present with multiple comorbidities atypical to traditional SCD diagnosis. These patients are older, use more opioids, and show signs of elevated tryptase levels, which could be an indicator of increased mast cell activation.

Interview with Wally R. Smith, MD, and Nina Kuei

Patients with sickle cell disease (SCD), or sickle cell anemia, typically suffer through episodes of vaso-occlusive crisis (VOE), ischemic events that usually require acute pain therapy. However, a subset of SCD patients develop chronic pain—something doctors are starting to learn more about.

These chronic pain patients tend to be older, use more opioids, and have noticeably high levels of mast cell activation, according to a new study presented at the 57th Annual Meeting of the American Society of Hematology (ASH), held in Orlando, Florida. The research could offer insights into why SCD patients develop chronic pain and may point to a novel biomarker for assessing SCD patients.

The study used pressure pain algometer readings and blood analysis to compare data among SCD patients with chronic pain (SCD-CP; n=12), those without chronic pain (SCD-NCP; n=17), and a control group of non-SCD African-American volunteers (n=9), reported lead author Nina Kuei, a second year MD candidate at the Medical College of Georgia at Augusta University.1 Earlier work conducted at the university had shown that SCD patients have more pain sensitivity compared to healthy controls.

The current study “took it a small step further and classified a portion of patients as either chronic or non-chronic,” Ms. Kuei explained. Chronic pain was defined as >50% of days reported as painful in pain diaries, which were collected over the span of 6 months. Interestingly, pain pressure algometer readings taken at 3 sites (trapezius, ulna, and masseter) did not show major differences between the SCD-CP and SCD-NCP patients. However, this does not necessarily indicate pain severity was similar between those with chronic pain and those without. “In order to make that conclusion, I would have to expand the study and match the two study groups by age,” Ms. Kuei told Practical Pain Management.

What Roles Does Age and Opioids Play?

Age appears to be a factor in the development of chronic pain among patients with SCD. According to the study, SCD-CP patients were older than SCD-NCP patients, with a mean age of 41 years compared with 32.2 years, respectively. This finding supports the hypothesis that as younger patients suffering from VOE  live longer, the nociceptive pain can evolve into neuropathic and centralized pain, creating the framework for chronic pain.

Another possible contributing factor, noted Ms. Kuei, was opioid usage among SCD-CP patients. Average morphine equivalents measured in milligrams per day were significantly higher for SCD-CP patients compared to SCD-NCP patients, at 11.45 mg/day versus 2.92 mg/day (P=0.015), respectively. The reasons behind this could have to do with dose escalation due to opioid tolerance or symptom severity. Or, it may be a clue that SCD patients can develop opioid-induced hyperalgesia.

Pain intensity and pain frequency have been shown to be higher for patients taking chronic opioid therapy. Those same patients have shown other relevant traits, such as negative coping, significant disease burden, SCD stress, and low mental and physical quality of life (QOL).2 While Ms. Kuei had access to dosage histories, it was still impossible to determine if that “paradoxical effect” of chronic opioid use on nociceptor receptor sensitization was a relevant factor in the SCD-CP patients’ pain pathologies, she noted.

“Opioid-induced analgesia seems to be a controversial topic, since some people strongly believe that it plays a strong role in explaining why chronic patients require increasingly higher dosage adjustments, while some do not believe it is an important factor at all. However, everyone can agree that at this point in our scientific knowledge, the cause of dose escalation for all patients on chronic opioids is a mystery,” she said.

Tryptase: A Warning Sign of Inflammation

While the debate continues over the relevance of opioid-induced hyperalgesia for SCD patients presenting with chronic pain, recent research is showing clear evidence that comorbid chronic inflammation could be a likely factor in why some SCD patients suffer more pain than others. Mast cell activation factors into sickle pathobiology and pain by promoting neurogenic inflammation and nociceptor activation through the release of substance P, a neuropeptide.3

Interestingly Ms. Kuei found substance P levels did not reach a statistically significant difference between the SCD-CP and SCD-NCP cohorts, (7221.1±7742.7 vs. 5983.1±3473.0 pg/mL, respectively). In the control group, substance P levels were 3939.7±1350.1 pg/mL, revealing an elevation in sickle patients at large.

Tryptase, on the other hand, appeared far more elevated in SCD-CP patients compared with SCD-NCP patients (1388.6 ±519.8 vs. 1023.64±221.04 pg/mL; P=0.00615). This difference appeared even greater compared to healthy controls (768.9±416.16  pg/mL; P=0.0053).

Tryptase, a serine proteinase found in mast cells, typically has been used as a biomarker for mast cell activation, though this is the first research to associate its elevation with chronic pain in SCD patients, according to Ms. Kuei. Mast cell activation syndrome (MCAS) presents a new context for doctors to better understand patients with comorbidities atypical to traditional SCD pathology. It may lead doctors to rethink how they manage symptoms for this patient group, she noted.

“A re-evaluation of SCD, and even chronic pain pathologies in general, is my ultimate hope for my research and other researchers with similar finding,” said Ms. Kuei. Given that studies are finding success with MCAS-targeted therapies to reduce pain, including hydroxyurea and c-kit targeted gene therapy,3,4 novel treatment approaches may not be far off. Alternative uses for imatinib and cromolyn could also be relevant, Ms. Kuei said, given that they are known to inhibit mast cell degranulation and stabilize mast cells, respectively.

“Using tryptase as a biomarker in emergency rooms, where oftentimes SCD patients are mistakenly identified as drug-seeking patients, would allow a more targeted approach to distinguishing a patient in the throes of a vaso-occlusive crisis from a chronic pain patient (this affects how the patient should be treated).”

The Evolving Framework of Pain in SCD

According to Wally R. Smith, MD, a professor of internal medicine at the Virginia Commonwealth University, mast cell activation is typical for sickle patients, although like pain, it does vary in its intensity. “The mast cell activity may not be a useful pain barometer because so many other sub-biologies contribute,” such as hypoxia-reperfusion, platelet activation, and inflammatory cascade involving selectins and inflammatory cytokines, for instance, he told Practical Pain Management.

It now seems plausible that older patients have more pain than younger patients, but this is probably not attributable directly to acute pain due to mast cell activation. Chronic neurological damage, central neuropathic pain due to continuing nociceptive stimuli—even environmental factors like colder temperature, barometric pressure, and wind speed—all suggest a multi-etiologic concept of evolving pain in SCD patients. So how exactly does mast-cell activation factor into SCD patients’ pain?

It is a question that remains unexplained. Dr. Smith hypothesizes that acute opioid use could be a practical “barometer” of SCD pain, but not vice versa, something he intends to explore in his own upcoming manuscript.

Ms. Kuei also hopes to continue her own investigations with the Medical College of Georgia, examining pain management therapies and helping to uncover new treatment approaches for SCD-CP patients. “My current work represents supportive evidence that maybe the concept of pain is more interconnected with other pathologies we already know about… there is some evidence out there, but we, as a medical community need to explore it further.”

The study was presented as part of an annual meeting of the American Society of Hematology. The original abstract can be found here. For more information about the society, click here. The study authors reported no relevant conflicts of interest

Last updated on: January 6, 2016
Continue Reading:
Long-term Opioids, Sickle Cell Disease, and Pain Patches

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