PAIN IN SICKLE CELL DISEASE

Introduction

Sickle cell disease (SCD) is a hereditary hemoglobinopathy and the most common hematological condition worldwide.¹ It is characterized by recurrent vaso-occlusion events that cause endothelial dysfunction and inflammation. Vaso-occlusive events result in painful attacks and progressive damage to tissues and organs. These conditions generate serious complications such as vasculopathy, as well as an acute thoracic syndrome or vaso-occlusive crisis.^2,3

Acute pain episodes are the most common complication of SCD. They increase in frequency with age, and a chronic pain syndrome evolves in 30%–40% of adolescents and adults with SCD and can significantly impair function.³

Etiologic and Pathophysiologic Classification

The major pain syndromes in SCD are categorized into those due to the disease itself (painful crisis, acute chest syndrome, priapism, splenic sequestration, aseptic necrosis or osteonecrosis, leg ulcers, vertebral body collapse), those associated with therapy (postoperative pain, iron overload) and those independent of the disease or its therapy (infection, trauma).⁴

Painful crises, or vaso-occlusive crises (VOCs), are not only the primary presenting morbidity associated with SCD, but also the cause of hospitalization in approximately 95% of cases. VOCs are associated with acute chest syndrome, hepatic and renal involvement, cerebrovascular accident, multi-organ failure and death. The most common sites of pain associated with VOCs are the lower back, joints, and extremities. The pain is usually sudden onset, throbbing and can last for a few days.⁴

Chronic pain in SCD is a debilitating complication that is associated with increased morbidity and mortality. It can be present in one or more sites, and usually presents as leg ulcers, avascular necrosis, bone infarcts, vertebral body collapse, or any combination of these.⁵

Sickle cell pain is primarily nociceptive, due to tissue damage and inflammation secondary to vaso-occlusion of the microcirculation by red cells. However available evidence in SCD includes demonstrated pathologic changes to the nervous system (e.g., altered cortical processing networks, altered biochemical structure and function of pain-sensing neurons), as well as patient-reported pain descriptors widely associated with neuropathic pain.⁶

Acute Pain Management

The fundamental approach to treat VOCs is prompt and adequate pain control (Table 1). In patients with moderate to severe pain, initial therapy is with opioids, preferably within the first 30 minutes of the crisis, in adequate and individualized doses. Morphine is the most indicated opioid in these cases, being available in most countries.³ Paracetamol and other anti-inflammatory drugs can also be used, mainly with the aim of reducing opioid requirement and adverse events.⁸

Adjuvant treatments include hydration, laxatives, antihistamines, antiemetics, intravenous fluids, and oxygen in the case of hypoxia. In some cases, anxiolytics may be used. Nonpharmacological approaches such as massage, acupuncture, yoga, and meditation can also be employed.⁸

Despite the importance of opioids in the treatment of acute pain crisis, they do not treat the underlying pathological processes and may be associated with hyperalgesia, tolerance, and addiction. Therefore, the prevention of pain associated with these crises is a recommended approach. Some drugs are used to reduce the frequency of attacks and the need for transfusion. Hydroxyurea has traditionally been used for this purpose, but it has several limitations such as adverse effects (skin ulcers, pancytopenia, diarrhea, rash, vomiting, nausea, anorexia, and thrombocytopenia) and consequently poor adherence. More recently, other therapies have been approved or are under development, such as supplementation with L-glutamine (decreases endothelial adhesion), crizanlizumab (humanized immunoglobulin G2 antibody inhibits P-selectin), rivipansel (pan-selectin inhibitor) and Voxelotor (inhibits HbS polymerization), which have the potential to enhance new protocols with the aim of reducing the impact of VOCs.³

Chronic Pain Management

SCD results in a progressive decrease in health-related quality of life over time due to the impact of disease-related complications and chronic use of opioids, generating a risk of stigmatization, which refers to a form of devaluation, judgment, or social disqualification of individuals based on a health-related condition. It can also lead to an inability to maintain consistent professional or school activity, to participate in daily social or recreational activities, and to participate in family life. In this context, a multidisciplinary team approach is required to adequately treat chronic pain in SCD, which includes psychosocial and mental

Table 1. Pain Management Strategies for Sickle Cell Disease

health providers, such as a social worker, behavioral health specialist, and community-based health worker (Table 1). A holistic patient centered approach is used that adequately addresses social determinants of health in addition to the medical complications that contribute to persistent pain.⁶

The chronic use of opioids is very common in patients with SCD, and this may be associated with episodes of withdrawal syndrome and dependence. In higher-risk patients, switching opioids, such as rotation to buprenorphine, is an option to consider.⁶

The presence of a neuropathic component in chronic pain in SCD should be addressed with appropriate neuropathic medications such as gabapentinoids, duloxetine, and tricyclic antidepressants.⁸ More recently, the use of cannabinoids in the treatment of chronic pain in patients with SCD has been investigated. The initial results seem promising; however, there are very few studies in this population and more solid evidence would be useful if cannabinoids are to be safely used in the treatment of sickle cell disease.⁹

PAIN IN ACUTE VARICELLA ZOSTER

Introduction

Herpes zoster (HZ) is a common medical condition that can have a major impact on the quality of life. It is caused by a reactivation of a latent varicella zoster virus (VZV). Treatment in the acute stage of the disease is aimed at reducing the duration of the episode, the impact on quality of life, and adequate pain treatment to reduce the occurrence of postherpetic neuralgia.¹⁰

The latent VZV is located in the dorsal root ganglia (DRG) after primary infection, usually in childhood. Its reactivation results in skin lesions and peripheral nerve inflammation. Hypoxic damage, neuronal loss, or injuries in the DRG may persist for months and further central sensitization may occur.¹¹ The latency of VZV is attributable to the body’s VZV-specific immune response. The virus reactivates more frequently in patients older than 50 years and immunocompromised patients.¹⁰

Diagnosis

Clinically, HZ typically presents with a unilateral skin rash that is limited to one dermatome.¹¹ Although the characteristic rash usually involves a single dermatome, it is not uncommon to find overlapping lesions that involve more than one segment. Multi-dermatomal herpes zoster affecting both sides of the body is rare.¹³ Individual lesions usually change from erythematous macules and papules to vesicles and pustules, sometimes forming crusts after 5 to 7 days. Typically, the lesions increase in number within 24 to 72 hours and spread across the affected dermatome in a radial fashion. Local lymphadenopathy may be observed. Some patients may develop hemorrhagic lesions. Herpes zoster most commonly affects thoracic dermatomes (55%), followed by the trigeminal region (20%) and cervical (11%), lumbar (13%), and sacral dermatomes (2%). Molecular detection of VZV DNA from skin lesions is considered the gold standard in the diagnostic of VZV infections, but it is indicated only if there are clinical doubts. Otherwise, the diagnosis is made clinically.¹⁰

Herpes Zoster Pain

The pain during the prodromal phase often gives rise to misdiagnoses because of the absence of characteristics skin lesions. Pain is often described as burning, stabbing, and pulsating.¹¹ For acute pain management, it is essential to distinguish the nature of the pain: nociceptive, neuropathic, or both.¹³ Acute, severe pain, and postherpetic neuralgia (PHN) are feared complications of HZ infection. The pain lasting for the first 30 days is known as acute herpetic neuralgia. When the pain is more severe, the likelihood of acquiring PHN is higher. Reduced exposure to recurrent painful stimuli and inflammatory factors throughout the acute phase of HZ may alleviate central sensitization and significantly lower the occurrence of chronic pain.¹⁴ Acute zoster pain occurs in more than 95% of patients more than 50 years old and 60%–70% of patients continue to have persistent pain 1 month after the acute episode.¹⁰

Treatment

The cornerstone for treating acute HZ is pharmacologic: antiviral drugs, corticosteroids, systemic analgesia, and, if pain persists, interventional pain techniques may be necessary.

Pharmacological Treatment

In patients without risk factors for complications, HZ is a self-limiting disease. Treatment objectives include the improvement of outcomes in terms of the quality of life, duration and extent of cutaneous symptoms, as well as intensity and duration of acute HZ-associated pain.

All patients presenting with HZ should receive antiviral pharmacological treatment early, preferably in the first 72 hours (Table 2). The European guidelines do not recommend initiating an antiviral medication in patients who have “uncomplicated” HZ (typical lesions, unilateral thoracic or lumbar HZ in patients younger than 50 years of age, without signs of a complicated course) who present more than 72 hours after the onset of skin symptoms.

Table 2. Antiviral Treatment Options for Acute Herpes Zoster Phase

The evidence on treatment for acute zoster pain is scarce. Controlling acute pain is supposed to diminish the incidence of PHN, although evidence from controlled studies to support this presumption is not yet available.

Adequate acute pain treatment in HZ is highly recommended. The somatic pain can be managed following the World Health Organization ladder directions. For the neuropathic pain, gabapentinoids may be considered. The positive effects of pregabalin and gabapentin on neuropathic pain has been confirmed in trials and meta-analyses. Pregabalin has the advantage of allowing more rapid incremental dose and earlier onset of pharmacological effect.¹⁰

Antidepressants inhibit the reuptake of norepinephrine and/or serotonin in the spinal cord, resulting in elevated transmitter levels that subsequently inhibit nociceptive spinal transmission. Amitriptyline, duloxetine, and venlafaxine can be used.¹⁰ Capsaicin is another option for treating neuropathic pain after the vesicles and erosions have healed. It is available as a patch formulation (8%).¹⁰

Early institution of an antiviral drug not only accelerates the healing of the rash but also reduces the severity of acute pain, thus reducing the incidence of chronic pain. Valacyclovir and famciclovir reduce the time to complete cessation of zoster-associated pain. Early institution of valacyclovir (within 72 hours) effectively inhibits viral replication, thus reducing the pathological impact on skin and nerves. Systemic corticosteroids can be considered in combination with antiviral drugs because they have marked anti-inflammatory effects leading to resolution of the acute inflammatory phase of the disease.¹²

Intravenous lidocaine infusion has been studied for treating PHN with good results for infusion during 5 days of 4mg/kg/h for 30 minutes.¹⁴

Minimally Invasive Procedures

Epidural steroid injections (ESI) have been used to treat HZ in the acute phase by reducing neuronal inflammation in the affected spinal nerves. A randomized controlled trial (RCT) demonstrated that an epidural steroid injection administrated in the acute phase results in pain relief of approximately 1 month. Transforaminal epidural injection (TFESI) seems to be more effective than ESI, with the medication going directly to the nerve root and the DRG.¹¹ Interlaminar ESI may not reach the anterior epidural space and does not result in such superior results as TESI. One study evaluates whether the earlier injection of steroids can reduce the incidence of PHN and concluded that the optimal period for the administration of epidural corticosteroids was 12 weeks. This result is consistent with previous findings that TFESI can prevent or decrease the risk of transition to PHN. A series of cases has been published with use of pulsed radiofrequency of the DRG as treatment for acute VZV not responsive to epidural steroid injections.¹¹

Pulsed radiofrequency of the nerves combined with intravenous lidocaine infusion was also shown to effectively relieve pain in patients diagnosed with HZ pain at the subacute stage.¹⁵

Another option is to perform ultrasound-guided blocks. The paravertebral block (PVB) is considered among the simplest and most time-efficient treatments for delivering analgesics. An RCT has been published recently comparing PVB and erector spinae pain block (ESPB) concluding that ESB and PVB were effective in controlling acute pain and persistent herpetic pain after 6 months, with ESPB being safer.¹³