Classification and Management of Acute and Chronic pain in Sickle Cell

Disease

1

Deepika S. Darbari, MDChildren’s National Medical Center

Professor of Pediatrics

George Washington University School of Medicine

and Health Sciences

Washington DC

Learning Objective:

• Pain in sickle cell disease can result from many underlying causes

• Phenotypes of pain in SCD may differ based on underlying mechanisms

• Pain taxonomy describing diagnostic criteria (AAPT and AAAPT) may be helpful in classifying pain phenotypes

• Understanding of pain phenotypes/mechanisms is crucial for selecting appropriate therapies for improving outcomes

Pain in sickle cell disease

• Most common complication

• Morbidity, direct and indirect cost , early mortality

Akinsheye et al. Blood 2011

All pains in SCD are not created equal!

Acute vaso-occlusive episodes

• Hallmark manifestation

• Acute Pain (Dactylitis). 6-8 months

• 5 cardinal signs of acute inflammation : – rubor (redness),

– calor (increased heat),

– tumor (swelling),

– dolor (pain),

– functio laesa (loss of function)

– Ischemia- reperfusion physiology (reperfusion injury)

Ischemia-Reperfusion Injury

Two distinct phases of Ischemia/Reperfusion:

• 1. Ischemia caused by interruption of vascular supply leads to tissue injury

• 2. Reperfusion is associated with resolution of occlusion and resupply of oxygen →inflammatory phase → systemic inflammation→ remote organ injury/ multi-organ dysfunction syndrome

Zhang et al. Blood 2016

Vaso-occlusion in SCDA multicellular and multistep model

Zhang et al. Blood 2016

Vaso-occlusion in SCDA multicellular and multistep model

Cells involved

• Sickle RBC

• Platelets

• Neutrophils

• Monocytes

• Endothelial cells

• Mast cells

Molecules/mediators • Pro-inflammatory

cytokines through the NF-kB pathway (TNF-α, ILs, endothelin-1, PG E2.

• Chemokines• Coagulation cascade• HMGB

Vaso-occlusion in SCD A multicellular and multistep model

Mechanisms underlying vaso-occlusion

• Vaso-occlusion in SCD arises from a complex cascade of interactions among RBCs, neutrophils, and endothelial cells

• Blockage of vasculature through multiple adhesive events

• Ischemia-reperfusion injury secondary to ongoing intermittent microvascular occlusions promotes chronic inflammation

Field et al. J pain. 2019

Acute Sickle Cell Disease Pain

Burden of Pain Increases with Age

Smith. Am Soc Hematol Education Program 2010

Vaso-occlusive episodes vs. daily pain

Smith et al Annals Int Med 2008

Smith W R et al. Ann Intern Med 2008;148:94-101

> 50% of patients experienced pain on >50% of the days;

30% experiened pain > 95% of the days

Episodes of daily pain

Chronic pain in sickle cell disease

Chronic SCD Pain

• Presence of SCD• Pain on most days in past 6

months• Display a sign on

exam/imaging• Not explained by other

diagnosis

• Modifiers: Chronic SCD Phenotypes

1) The Chronic SCD pain without contributory disease complications

2) Chronic SCD pain with contributory disease complications

3) Mixed pain type

Neuroplasticity/ Central sensitization

Latremoliere and Woolf. J Pain. 2009

Central sensitization: Increased responsiveness of nociceptive neurons in the central nervous system (increased sensitivity)

Characterized by reduction in pain thresholds and expansion of receptive field of the motor neurons

Changes occur in - Neurons in the dorsal horn cells-Spinal nucleus pars caudalis-Thalamus, amygdala and - Ant. cingulate cortex

Could be triggered by inflammation

Multiple Cellular Processes that Lead to Central Sensitization

Latremoliere and Woolf. J Pain. 2009

Hyperalgesia and after sensations in patients with SCD vs. matched non-SCD controls

Darbari et al. Scan J Pain 2017

Differences in brain connectivity patterns by pain burden

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High pain group: Greater pronociceptive connectivity (Panel A)

• Greater connectivity between pro-nociceptive structures such as the insula and secondary somatosensory cortex.

• Greater connectivity between DMN regions and pro-nociceptive pain structures

Low pain group: Greater antinociceptive connectivity (Panel B)

• Greater connectivity between the primary somatosensory cortex and an antinociceptive region of the cingulate (subgenual) (associated with endogenous analgesic mechanisms)

Darbari et al. J Pain 2015

Chronic persistent/daily pain of SCD • Chronic (> 3 months) pain is common

• Starts in adolescents and young adult years

• Comorbidities (poor sleep, anxiety, depression)

• SCD complications +/- (avascular necrosis, leg ulcer)

• Poor response to standard therapy

• Underlying mechanisms are not completely clear: recurrent VOC, neuropathic pain, sensitization of central/peripheral nervous system →altered pain processing/ perception → spontaneous pain

Field et al. J pain. 2019

Mechanisms and modulators of acute and chronic SCD pain

SCD Pain Phenotypes

Peripheral

(nociceptive)

Peripheral

neuropathic/

sensitization

Central neuropathic/

sensitization

Underlying

mechanism

Inflammation or

mechanical damage of

tissues

Damage or dysfunction of

peripheral nerves

Altered central pain processing

Pain

characteristics

Throbbing, sharp,

pounding, dull

Local

Burning, heavy sensation, or numbness along the path of the affected nerve. Allodyniaand hyperalgesia

Hyperalgesia/allodynia

Diffuse pain

Response to

therapy

NSAID, opioid responsive Responds to both peripheral

and centrally acting

pharmacological therapies,

gabapentinoids

Responsive to neuroactive

compounds altering levels of

neurotransmitters of pain

Classic

examples

Osteoarthritis

Rheumatoid arthritis

? SCD acute VOC

Diabetic neuropathic pain

Post-herpetic neuralgia

SCD -related

peripheral

neuropathies

? SCD persistent pain

Fibromyalgia

Irritable bowel syndrome

TMJD, Tension headache

? SCD chronic pain

Darbari et al. EJH.2014

Suggested Management of Pain by Phenotypes

Evidence-based management of sickle cell disease: expert panel report, 2014

Acute Pain

Management

Guidelines 2014

• Treat promptly/ aggressively

• Reassess and individualize

• Non-opioids (anti-inflammatory)

• Opioids/ PCA

• Use non-pharmacologic

modalities (heat)

Chronic Pain

Management

Guidelines

Evidence-based management of sickle cell disease: expert panel report, 2014

• Etiology of pain

• Believe patient report

• Individualize

treatment plan with

the patient

• Evaluate patient

regularly

• One primary provider

for opioids

• Manage opioid side

effects

• Treat comorbidities:

Psychiatrist, addiction

specialist, social

worker

• Non-pharmacologic

adjuvant therapy

Chronic pain in SCD • While many patients may have chronic pain associated with

AVN/ leg ulcers etc. there is often no anatomic correlate to explain the pain

• Likely due to a different mechanism than vaso-occlusion/ disease complication alone

• Pathophysiology not completely clear but could be related to nerve damage, sensitization, inflammation, and/or opioid use

• Central sensitization associated with opioid use and psychological comorbidities and traits can contribute to a chronic pain phenotype.

• Patients may report exacerbations (or “crises”)

Field JJ 2017 ASH

1. Focus resources on adults with chronic pain (high rates of utilization for pain)

2: Aggressively treat SCD/ any underlying causes of pain- AVN- HU- Chronic transfusion

3: Apply principles of chronic pain management/ opioids.

Higher doses/ larger quantities of oral opioids do not help

Managing comorbidities

• Psychological co-morbidities are common in patients with chronic diseases including SCD

• Depression, anxiety, poor sleep quality are often present especially in patients with high pain burden

• Certain traits such as catastrophizing can make individuals at higher risk for developing chronic pain

• Parents with catastrophizing can increase the risk of high pain burden in child in SCD

• Co-morbidities can contribute and make pain worse

• Managing comorbidities is necessary

Chronic pain in SCD: Current gaps

- Risk factors / predictors of chronic pain

- Mechanisms/ central sensitization

- Role of opioid

- Long term effect of therapy on development of chronic pain (HU, Chronic transfusion, opioids)

- Impact of early HSCT

- Role of adjuvant therapies

- Non-pharmacologic approaches

- Endpoints/ biomarkers for therapeutic trials ( PRO/non-PRO)

Integrative Approaches for Managing pain

CDC data:Nationwide opioid crisis

Deaths due to opioid pain relievers in the united

states from 1999-2013 appears to be lower than

other non-cancer disorders (adults)

OPR: Opioid Pain Reliever

Cause of Death Due to all causes Due to OPR Percentage

Heart Disease 20,595,492 21,656 0.11

Fibromyalgia 3,282 144 4.4

Low Back Pain 3,758 80 2.1

Migraine 2,286 103 4.5

Sickle Cell Disease

12,261 95 0.77

Pain Medicine 2016; 17:1793

Slide courtesy Dr. Ballas

J Natl Compr Canc Netw. 2020 Apr;18(4):392-399 2020

Integrative Medicine Clinic for SCD

• Multi-disciplinary clinic held in the division of Hematology

• Comprehensive Services:

• Hematology

• Pain management

• Psychology

• Social work

• Physical therapy

• Healing touch

• Aromatherapy

• Massage therapy

• Acupuncture/Acupressure

Disease modifying

Rx

Counselling

Physical therapy

AcupunctureAroma

Psychosocial

Mind body

Integrative care for sickle cell

pain

Complement Ther Med. 2020;49:102287.

Summary and conclusions

• Pain/chronic pain is common in sickle cell disease

• Pain phenotypes may vary based on underlying etiology

• One or more mechanisms may be active at a given time in a patient ( AAPT modifiers)

• Management of chronic pain is a long process

• Be cognizant of opioid related comorbidities

• Use principles of managing sickle cell disease and chronic pain to effectively manage a patient with SCD and chronic pain

Thank you!

ddarbari@childrensnational.org

Questions?