Sickle cell disease and pain

Sickle cell disease (SCD), is the name of a group of blood diseases that affect hemoglobin. It is a lifelong hereditary blood disease that affects 20 million people worldwide. (NIH National Heart, 2024) Its name comes from the sickle-shape erythrocytes (red blood cells) that are part of the disease. The rigid, sickle cell shape prevents the blood cells from moving easily through blood vessels causing vaso-occlusive crises which can lead to distal ischemia, infections, retinopathy, pain, as well as strokes.

The spectrum of pain

For people with SCD, pain is a predominant symptom which can come in episodical presentation, as well as chronic pain. While there are there are variations in the experience of the pain, pain crises are universal to the disease. Pain crises are acute recurring episodes of pain. Vaso-occlusion and impaired oxygen supply (inflammatory pain) are the most common causes of acute nociceptive pain, which can affect both children and adults. (Hyacinth, 2020)

If we look at the pain suffered by those with SCD, and place nociceptive pain on one side of the spectrum, neuropathic pain would be at the opposite end of the spectrum. Inflammatory nociceptive pain, which is generally acute, can be treated with non-steroidal anti-inflammatory drugs (NSAIDs) or, if necessary, opioids. Neuropathic pain, stemming from central mechanisms like stroke, or from ischemic damage to nerves, is more complex and the treatment regimen is not straightforward. (Hyacinth, 2020) (Molokie, 2020).

Impact of pain on QoL

In an observational study by Santos, et al. 69.7% of adult patients with SCD were found to have neuropathic pain based on the Douleur Neuropatique Questionnaire (DN-4). Furthermore, the SCD patients experiencing neuropathic pain had significantly worse scores across all domains of quality of life measured with the World Health Organization Quality of Life – brief questionnaire (p < 0.05). (Santos, 2021)

Since SCD patients frequently require complex medical regimens to manage their illness, it is these medical regimens that become the focal point of their treatment, while the patient’s ability to function receive less attention. It is not surprising that frequent and severe pain episodes can be debilitating and have a negative impact on daily functioning. It is also not surprising that when compared to healthy children, children with SCD score lower on health-related quality of life (HRQOL). (Hyacinth, 2020).

The measurement of pain in patients with SCD vs healthy controls

Hyacinth et al. performed thermal QST on 48 children and adolescents suffering from SCD. They found that 27% of these children had abnormal sensory findings in terms of cold, warm sensation, or heat pain thresholds as compared to normative data. Interestingly, these children had higher frequencies of clinic admissions due to vaso-occlusive pain crises than children with normal sensory patterns, even though the clinical pain at the time of testing in both groups was equal (Hyacinth, 2020).

Molokie, et al. compared responses to standardized thermal stimuli  among 186 African American patients with SCD pain to a healthy matched control group. Participants were tested using Medoc’s TSA-II with 30*30 mm thermode. The Method of Limits, without overlapping test areas at a slow rate of 0.5°C/sec., was used to identify cold sensation (CS), warm sensation (WS), heat pain (HPT) and cold pain thresholds (CPT). They were tested at 2 painful sites as well as 1 non-painful reference site, out of 6 optional sites in total. Whenever possible, the anterior forearm was used as the reference site for both the SCD patients and the healthy participants. In this way, the researchers were able to accomplish quantitative assessment of small-caliber (A-δ and C fiber) sensory nerve function. They strived for the patients’ pain sites tested to be on the opposite side of their body from the reference site. Three to five repetitions were conducted at each site and the three closest measurements were averaged to identify the cold pain threshold and heat pain threshold. (Molokie, 2020) 

Sensitization was defined as HPT or CPT within 0.5°C of baseline for the upper extremity, and 1.5°C for the lower extremity, or these thresholds rated as 6/10 in pain intensity on the Pain Intensity Number Scale (PINS). The percentage of SCD patients showing sensitization at the reference site to at least one type of stimulus, was 23%, while only 12 % for the control group. This difference between the SCD patients and controls was the statistically significant across all sites The groups were also compared for any sensitization across the 3 tested sites; these findings were also statistically significant. The prevalence of sensitization among SCD patients was 32% versus, 16% for the controls (P = .004). In other words, the researchers found higher incidence of sensitization (allodynia and hyperalgesia) in SCD, pointing to a neuropathic component in in this disorder. (Molokie, 2020) 

Implications for the SCD patient

We now know that patients with SCD may suffer more than one type of pain. There is the pain from acute sickle cell related problems, such as leg ulcers or avascular necrosis and they may also suffer from acute pain crises of inflammatory or ischemic pain. (Hyacinth, 2020). The presence of a neuropathic component to their pain, associated with abnormal thermal thresholds, as indicated by the incidence of allodynia and hyperalgesia during QST, is important to note.  (Molokie, 2020; Hyacinth, 2020) 

While the pain from inflammatory origins, as well as the acute pain crises, may be treated with NSAIDs and/or opioids, neuropathic pain treatments are less straightforward. The use of Quantitative sensory testing on SCD patients broadens the clinician’s ability to identify neuropathic pain and prescribe treatment to target the mechanisms associated with neuropathic pain, offering these complex patients the possibility of a better Quality of Life.  (Molokie, 2020)

References

Hyacinth, O. S.-R. (2020). Pain Experience, Physical Function, Pain Coping, and Catastrophizing in Children with Sickle Cell Disease who had Normal and Abnormal Sensory Patterns . Journal of Pain and Symptom Management, 1079-1091.

Molokie, R. E.-R. (2020). Molokie, R. E., Wang, Z. J., Yao, Y., Powell-Roach, K. L., Schlaeger, J. M., Suarez, M. L., & Wilkie, D. J. (2020). Sensitivities to thermal and mechanical stimuli: adults with sickle cell disease compared to healthy, pain-free African American contro. The Journal of Pain, 957-967.

NIH National Heart, L. a. (2024, April 22). Sickle Cell Disease - What is Sickle Cell Disease? Retrieved from NIH: https://www.nhlbi.nih.gov/health/sickle-cell-disease

Santos, L. F. (2021). Impact of neuropathic pain on quality of life in adults with sickle cell disease: observational study. Hematology, Transfusion and Cell Therapy, 263-267.