Complex regional pain syndrome (CRPS) is a condition which can develop in individuals who have had some form of trauma to a limb (after injury or surgery). The condition is characterised by limb-specific pain, which is disproportionate in magnitude and duration to more typical pain responses post-tissue trauma. In some cases, the pain is spontaneous, without any cause. This is believed to be due to dysfunction of the central and peripheral nervous systems, more specifically, the autonomic nervous system. Subtle damage to the sensory nociceptors (pain receptors) and, therefore, how pain is processed is responsible for the initiation of the chronic neuropathic pain pathway. CRPS is distinguished from other forms of chronic pain conditions as excessive pain is accompanied by inflammatory changes in the affected limb regions as well as an array of secondary symptoms such as temperature changes and swelling of the skin. The pathology of the condition can be understood in two forms: Acute CRPS and Chronic CRPS. These subsets differ in their symptom manifestation and duration, with a small subset of patients with acute CRPS transitioning into chronic CRPS. For those with acute CRPS, their symptoms may improve over time, but chronic CRPS cases can be severely disabling. As the exact causal mechanism behind CRPS is unknown and the symptoms it presents greatly vary amongst patients, it can be a condition that is difficult to treat.
Subtypes of CRPS
Type 1 CRPS
Also called sympathetic dystrophy, this form of CRPS occurs without known nerve damage.
Type 2 CRPS
Also called causalgia, this form of CRPS is the result of damage to a specific nerve.
This refers to the recent onset of short-term symptoms. At this acute stage of the syndrome, inflammatory features are dominant.
- Warm, complex regional pain syndrome: Increased skin temperature at symptom onset as well as red skin, oedema and increased sweating from the affected limb.1 Approximately 70% of patients report a warm subtype at first presentation.2
At the chronic stage, autonomic features dominate.
- Cold complex regional pain syndrome: Display pale or blue skin colour where skin temperature is significantly colder. Also characterised by features of autonomic nervous system dysfunction (i.e. inappropriate pain response to stimuli)
Causes of CRPS
Recent research on CRPS suggests that there isn’t just one single mechanism responsible for its onset.3 Rather, the syndrome is caused by multifactorial processes, with the relative contributions of these different mechanisms varying across patients. CRPS symptoms in patients who have not had limb trauma have been reported, but only a small number of cases. In instances where CRPS is triggered following limb injuries, possible mechanisms include:
Triggering of pro-inflammatory and immune responses
B cells are regulatory immune cells responsible for protecting against infection and disease. Interleukins are expressed by white blood cells as cell signalling molecules.4 Post-limb injury and elevated activation of these two immune responses are possibly responsible for the development of CRPS.
Central and peripheral nociceptive sensitisation
Central and peripheral sensitisation is thought to be responsible for the clinical CRPS observation of pain remaining long after the initial pain stimulation has subsided. After tissue or nerve injury:
- Central nervous system sensitisation: Results in increased excitability of nociceptor neurons, which increases the responsiveness to pain.
- Peripheral nervous system sensitisation: Involves local changes which decrease the stimuli threshold required for nociceptors to respond. This leads to an increase in the background firing of nociceptors in response to normally painful stimuli.
These two forms of sensitisation are responsible for CRPS symptoms such as:
- Hyperalgesia: abnormally heightened sensitivity to pain
- Allodynia: Pain from a stimulus that does not normally provoke pain
It is also of note that central and peripheral nociceptive sensitisation is mediated by the release of inflammatory cytokines, which perpetuate the sensitisation.
Recent functional MRI studies suggest that there are several brain changes which are associated with CRPS.5 Whether these are strictly linked to CRPS cause is less known, but they do indicate a role in sustaining CRPS. One of the observations which have been made is that the parts of the brain which are responsible for representing your sensory experiences (somatosensory cortex) show changed morphology.6 The part of the somatosensory cortex that is associated with the affected limb appears to shrink, and the degree of the alteration corresponds to the patient’s pain intensity.
Genetic and psychological factors
The varied clinical symptoms of CRPS make finding genetic triggers for CRPS difficult. Some studies have identified polymorphic genes which encode receptors of the HLA system, as possibly being associated with CRPS onset. However, these are still preliminary associations which require more extensive studies for conclusive findings. Psychological factors were previously widely considered to be involved in CRPS development; however, now, psychological factors alone are not considered to be causal factors for CRPS. Instead, there is evidence of comorbidity. For example, psychological distress such as anxiety in conjunction with physical injury might affect the later development and severity of CRPS. This might be due to the effect of psychological distress on sympathetic nervous system arousal.7 As with genetics, psychological factors are not causal but rather present as factors which may exacerbate the symptoms of CRPS.
Signs and symptoms of CRPS
- Allodynia or Hyperalgesia: Allodynia is pain due to a stimulus that does not normally provoke pain. Hyperalgesia is the exaggerated response to a normally painful stimulus. A burning sensation may accompany chronic pain
- Temperature asymmetry: In the warm subtype, the affected limb is warmer relative to other parts of the body. In the cold subtype, the opposite is observed
- Skin colour asymmetry: In some cases, the affected limb region can appear blotchy, purple, pale or red
- Trophic changes: Pitting of the nails as well as abnormal hair growth in the affected limb. In some cases, the skin may become shiny and thin and in others, thick and scaly.
- Motor changes: Limited range of motion in the affected limb
- Asymmetric oedema: Swelling caused by fluid buildup in the affected limb can also cause stiffness
Management and treatment for CRPS
The symptoms of CRPS show great variation both amongst individuals and throughout the disease progression. Therefore, there is a similar variation in the treatment options utilised for management.8
Physical and occupational therapy
One of the symptoms of CRPS and sometimes causes is kinesiophobia (the fear of motion) which can lead to the worsening of CRPS as the affected limb stiffens. Physical and occupational therapy forms such as isometric strengthening exercises, electrotherapy, and mirror therapy can provide great rehabilitation support. This can significantly improve pain and the quality of life for CRPS sufferers.
A variety of medications have been used for symptomatic pain management of CRPS, although the type of medications used have changed over time. Bisphosphonates have commonly been used as they play a role in modulating inflammatory responses. Sympathetic blocks, which involve an injection of both anaesthetic and anti-inflammatory medications, are also used. As continued research uncovers a better understanding of the underlying molecular mechanisms, new pharmacotherapies are being developed for a more targeted approach.
Transcranial magnetic stimulation
A safe and non-invasive treatment which produces a brief magnetic pulse into the brain, high-frequency stimulation has been shown to reduce pain beyond 1 week.
Surgical treatment is often opted for by patients to avoid excessive use of opioids. Therapies such as spinal cord stimulation, implantable peripheral nerve stimulation and dorsal root ganglion stimulation all generally work to target the chronic pain, postural-related, and functional symptoms of CRPS.
Diagnosis of CRPS
Diagnosis of CRPS tends to follow the Budapest Criteria, which is now a universal clinical tool due to its high degrees of specificity.9 Typically, limb trauma precedes the clinical symptoms of CRPS. Spontaneous CRPS is rare and should be diagnosed with extensive clarification.2
Patients must exhibit at least one symptom in 3 of 4 categories and 1 sign in 2 or more categories.10
|Evidence of hyperalgesia to pinprick
Allodynia to light touch
|Change in: Skin/ColourTemperature
|Evidence of temperature asymmetry and skin colour changes
|Change in: Sweating/Edema
Decreased Range of motion (ROM)
Change in trophic factors
|Evidence of decreased ROM
Motor dysfunction in the form of weakness and tremors
Trophic changes in hair, nails and skin
The outcomes of CRPS show great variability. In most cases, patients may recover over months/years as the injured nerve regrows; however, if this doesn’t happen, then the condition could have a long-term disabling effect. In individuals who experience prolonged disability despite treatment, this is usually an indication of separate underlying problems.
CRPS is a condition which can develop in individuals who have experienced some form of limb trauma. Type I CRPS exhibits symptoms unrelated to nerve injury, whereas Type II CRPS results from direct nerve damage and sensitisation. Hyperplasia, allodynia and inflammation are the common characteristic symptoms of the condition, which, if left untreated, can have serious long-term long-term disabling effects. However, as research in understanding the exact molecular and cellular mechanisms of CRPS continues, forms of more targeted therapy to treat and manage CRPS are in the works.
Can CRPS be prevented?
As the exact cause behind CRPS is not clear, prevention of CRPS is not possible. Early intervention in therapy and reducing risk factors are key in the management of CRPS.
Who is at risk of CRPS?
Some papers have established certain risk factors such as being assigned female at birth (AFAB), and existing conditions of fibromyalgia and rheumatoid arthritis.8
How common is CRPS?
CRPS occurs most frequently in people of European ancestry (66-80% of cases). In the US, CRPS type 1 developed in 5.46 in 100,000 people each year.
When should I see a doctor?
If you observe any of the symptoms mentioned above, it's a good idea to consult a physician to see if your symptoms align with a CRPS diagnosis.
- Bruehl S, Maihöfner C, Stanton-Hicks M, Perez RSGM, Vatine JJ, Brunner F, et al. Complex regional pain syndrome: evidence for warm and cold subtypes in a large prospective clinical sample. Pain. 2016 Aug;157(8):1674–81.
- Birklein F, Dimova V. Complex regional pain syndrome–up-to-date. PAIN Reports. 2017 Dec [cited 2023 Jun 15];2(6):e624. Available from: https://journals.lww.com/painrpts/Fulltext/2017/12000/Complex_regional_pain_syndrome_up_to_date.8.aspx
- Guthmiller, Kevin B., and Matthew Varacallo. “Complex Regional Pain Syndrome.” PubMed, StatPearls Publishing, 2020, www.ncbi.nlm.nih.gov/books/NBK430719/
- Justiz Vaillant, Angel A., and Ahmad Qurie. “Interleukin.” PubMed, StatPearls Publishing, 2022, www.pubmed.ncbi.nlm.nih.gov/29763015/#:~:text=Interleukins%20(IL)%20are%20a%20type
- Goebel, Andreas. “Current Concepts in Adult CRPS.” Reviews in Pain, vol. 5, no. 2, June 2011, pp. 3–11, https://doi.org/10.1177/204946371100500202.
- Kaas, J. H. “Somatosensory Cortex - an Overview.” Www.sciencedirect.com, 2004, www.sciencedirect.com/topics/psychology/somatosensory-cortex.
- Bruehl S. Complex regional pain syndrome. BMJ. 2015 Jul 29 [cited 2023 Jun 14];h2730. Available from: https://www.bmj.com/lookup/doi/10.1136/bmj.h2730
- Taylor SS, Noor N, Urits I, Paladini A, Sadhu MS, Gibb C, et al. Complex regional pain syndrome: a comprehensive review. Pain Ther . 2021 Dec [cited 2023 Jun 15];10(2):875–92. Available from: https://link.springer.com/10.1007/s40122-021-00279-4
- Kim, Young-Do. “Diagnosis of Complex Regional Pain Syndrome.” Annals of Clinical Neurophysiology, vol. 24, no. 2, 31 Oct. 2022, pp. 35–45, www.e-acn.org/journal/view.php?number=618 .
- Stanton‐Hicks M. Complex regional pain syndrome. In: Lynch ME, Craig KD, Peng PW, editors. Clinical Pain Management. 1st ed. Wiley; 2022 [cited 2023 Jun 15]. p. 381–95. Available from: https://onlinelibrary.wiley.com/doi/10.1002/9781119701170.ch37