Chronic Post-Surgical Pain

The most pertinent curriculum item is:"Explains the risk factors for persistent post-surgical pain including measures to minimise its occurrence".

This topic was an SAQ in 2017, where marks were for: definition, most common causative surgeries, risk factors, and the pathophysiological changes at spinal cord level.

It has since come up as a CRQ in 2020 (pass rate 61%) and 2023 (66%); spinal cord pathophysiology (central sensitisation and wind-up) is not answered as well as other elements of the question.

Resources

Chronic post-surgical pain (CPSP) is an increasingly common phenomenon, with important personal, healthcare and economic consequences

Quoted incidence varies widely depending on the definition used and the time-point of follow-up:

Any pain (lenient definitions): 10 - 50%
Severe pain (>5/10): 5 - 10%
Incidence falls the longer patients are followed up

Incidence also varies by surgery: lower after inguinal hernia repair and caesarean section (~10%), higher after amputation and CABG (30 - 50%)

Unlike traumatic injury, elective surgery is a predictable insult; this provides an opportunity for risk stratification and prevention

CPSP is defined in ICD-11 as:

Pain which develops, or increases in intensity, after a surgical procedure or tissue injury
Persisting beyond the healing process (>3 months after the triggering event)
Localised to the surgical area or a related innervation territory (i.e. an area projected onto the innervation of a nerve involved in the surgical area, or a dermatome or Head's zone)

Also requires:

Other causes of pain to be excluded (e.g. infection, malignancy, pre-existing pain conditions)
If pain was present pre-operatively, it must be different in character or intensity
Caused by tissue trauma arising from a surgical procedure (as opposed to uncontrolled/accidental damage e.g. trauma)

The degree of tissue or nerve damage alone cannot explain the variation between individuals undergoing the same surgery
Risk is best understood through a biopsychosocial model; there are patient, surgical and pain-related risk factors

Patient factors

Biological

Younger age
Female sex
Genetics: polymorphisms in genes involved in dopamine neurotransmission (e.g. COMT, GCH1) can raise or lower risk
Smoking
Raised BMI

Psychological

Anxiety and depression
Pain catastrophising
Sleep disturbance
Somatisation
Poor coping strategies and negative expectations

Social

Low socio-economic status and educational level
Poor access to healthcare
Previous addiction or disability
Good social support appears to be protective

Surgical factors

Type of surgery

Type of Surgery	Incidence of CPSP
Amputation	30 - 85%
Thoracotomy	5 - 67%
Inguinal hernia repair	17 - 21%
Knee arthroplasty	13 - 44%
Mastectomy	11 - 64%
Hip arthroplasty	7 - 23%
Sternotomy	7 - 50%
Caesarean section	6 - 18%
Craniotomy	7 - 65%

Other surgeries at higher risk are those which are:

More traumatic (i.e. open vs. laparoscopic/endoscopic)
Of longer duration
A repeat/re-do surgery
Responsible for intra-operative nerve injury
Performed by a less experienced surgical team
Beset by post-operative complications (BJA, 2022)

Pain-related factors

Pre-existing pain or greater generalised pain sensitivity

Includes chronic pain conditions such as fibromyalgia, migraine or chronic back pain
Includes chronic opioid use and opioid dependence

Acute post-operative pain of increased intensity and/or duration, particularly if visceral or neuropathic in nature

This is one of the strongest predictors of CPSP
Acute pain is itself a product of all the other biopsychosocial factors, so it may be a correlate of CPSP rather than a true independent predictor

High-dose intra-operative opioids (particularly remifentanil) may cause opioid-induced hyperalgesia, increasing acute pain scores and analgesic requirement

Prediction

One predictive model (BJA, 2022) found CPSP can be fairly reliably predicted by the combination of:

Requirement for pre-operative opioid treatment
Bone surgery
The pain score at day 14 post-operatively
The presence of painful cold sensation at the surgical site at day 14 post-operatively

Psychosocial risk can be assessed peri-operatively with validated questionnaires, e.g. the pain catastrophising scale

A surgical incision may produce three distinct types of pain to varying degrees:

	Nociceptive	Inflammatory	Neuropathic
Mechanism	Activation of high threshold nociceptors (C and Aδ fibres) by injury to non-neuronal tissue	Release of inflammatory mediators by local immune and stromal cells	Direct injury to neuronal structures
Example	Surgical incision	Heat, redness and swelling of the wound	Cutting, diathermy or devascularisation of a nerve
Response	Adaptive	Adaptive	Maladaptive
Plasticity	Reversible	Generally reversible	Variably reversible
Sensitisation	Peripheral	Peripheral and central	Peripheral and central

Peripheral sensitisation

A reduction in the activation threshold of nociceptors that innervate inflamed tissue
Ongoing stimulation, acidosis and inflammation at the wound lead to increased excitability and spontaneous (ectopic) firing of peripheral nociceptors
Altered gene expression in the dorsal root ganglion causes longer-lasting excitability

Central sensitisation

An increase in excitability of neurones in the CNS, driven by continued nociceptive input from the periphery
At the dorsal horn, repeated C-fibre input activates NMDA receptors, leading to the 'wind-up' phenomenon and heightened pain sensitivity
Microglial and immune cell activation in the spinal cord contribute to the extent and duration of pain
Supraspinal changes, including altered descending pain modulation, help maintain the chronic state

Pain can be neuropathic, nociceptive or a mixture
The central sensitisation in CPSP leads to typical neuropathic symptoms in 35 - 57% of patients, such as:

Allodynia
Hyperalgesia (whose presence may be predictive of a prolonged neuropathic pain)
Dysaesthesia

Although the incidence of neuropathic pain varies by surgery, it is commonest after:

Thoracotomy: intercostal nerve damage
Mastectomy: intercostobrachial or axillary nerve injury
Amputation

Perioperative Strategies to Reduce CPSP

Prevention should begin at pre-operative planning and extend into the recovery period
It combines less invasive surgery, multimodal analgesia (including regional anaesthesia) and attention to biopsychosocial factors

Risk assessment

Identify high-risk patients using the risk factors above
Screen for psychosocial risk, e.g. anxiety, depression, catastrophising
Individualised procedural risk stratification

Optimisation

Optimise pre-existing pain and review chronic opioid use
Patient education and setting realistic expectations
Psychological support and behavioural interventions to improve coping
Plan an analgesic strategy (including regional anaesthesia) and discuss it with the patient

Surgical technique

Minimally invasive approaches
Nerve-sparing technique
Reduced operative duration

Anaesthetic technique

Regional anaesthesia wherever appropriate (see below)
Multimodal analgesia targeting several points on the pain pathway (see below)
Avoid high-dose intra-operative opioids (especially remifentanil) to minimise opioid-induced hyperalgesia

Mechanism

Regional anaesthesia (RA) is considered the centrepiece of multimodal prevention, as it acts at several points on the pain pathway:

Blocks nociceptive input at the periphery
Reduces input reaching the spinal cord and higher centres, preventing central sensitisation
Local anaesthetics have anti-inflammatory properties: they reduce ectopic firing, cytokine release and neutrophil priming
Reduces opioid requirement, and therefore opioid-induced hyperalgesia

Evidence by surgery type

Overall, meta-analyses suggest a benefit, but individual trial results are mixed

Surgery	Techniques shown to favour prevention of CPSP
Breast surgery	Paravertebral block, IV lidocaine, local infiltration/continuous wound infusion (PECS 2 evidence mixed)
Thoracotomy	Epidural (greatest effect); paravertebral likely equivalent
Caesarean section	TAP block, continuous wound infusion, intraperitoneal local anaesthetic
Iliac crest bone graft	Local wound infiltration/continuous wound infusion
Amputation, laparotomy	Epidural

Evidence for other procedures (cardiac, hernia repair, prostatectomy, hysterectomy) is limited and less clear

Why is the evidence mixed?

Most patients do not develop CPSP, so many trials are underpowered
Heterogeneous patients who are not stratified by biopsychosocial risk
Varying definitions, follow-up times (6 - 55 months) and outcome measures
Different block techniques, adjuncts and surgical techniques; block success often not reported
As RA becomes standard practice, it is ethically difficult to have a control group that receives none

Multimodal analgesia uses several drugs simultaneously to target different points on the pain pathway, giving additive (possibly synergistic) effects with fewer side-effects from any single agent

Target	Intervention
Peripheral nerve activation and sensitisation	RA, local anaesthetics, gabapentinoids
Local inflammation	RA, NSAIDs, COX-2 inhibitors, paracetamol, dexamethasone
Central sensitisation	RA, NMDA antagonists (ketamine, magnesium), α₂-agonists, corticosteroids, opioids
Limbic system and cortical processing	Antidepressants, anxiolytics, behavioural interventions, support and expectation-setting

Evidence for individual agents

The most effective agents for reducing the incidence and severity of CPSP at six months (BJA, 2023) are:

Ketamine

NMDA antagonist; reduces wind-up and acute opioid tolerance
Infusions for at least 24 h have reduced pain at 3 and 6 months
May be particularly beneficial for patients on long-term pre-operative opioids

IV lidocaine

Reduces inflammatory and neuropathic nociception and central sensitisation
Meta-analysis showed reduced CPSP at 3 - 6 months, in both breast and non-breast surgery

Gabapentinoids

Act on the α₂δ subunit of voltage-gated calcium channels, which are upregulated during central sensitisation
Recent meta-analyses do not support peri-operative use to prevent CPSP; effective doses also cause sedation and gait/visual disturbance
They do, however, have a role in treating established neuropathic pain

Dexmedetomidine

Limited human data; infusion during breast surgery reduced pain intensity at 3 months
Useful as an opioid-sparing agent and as a perineural adjunct to prolong blocks

Others

NSAIDs/COX-2 inhibitors and paracetamol: integral to acute pain management, but no RCT evidence that they reduce CPSP
Duloxetine: may reduce post-operative pain 12 weeks after surgery
Memantine: one positive RCT after mastectomy
Inadequate literature to comment on clonidine, magnesium or nefopam

Acute pain control

Effective control of acute pain, as its severity and duration are closely linked to CPSP
Continue regional techniques and multimodal analgesia where appropriate
Early recognition and treatment of neuropathic features (e.g. allodynia, hyperalgesia)
Minimise opioid use; new persistent opioid use at 3 months affects ~5% of opioid-naïve patients and shares many risk factors with CPSP

Follow-up

An MDT approach with physiotherapy, psychotherapy and patient education
Transitional pain services reduce long-term analgesic and opioid use (BJA, 2021)
Established CPSP should be managed as for other chronic pain, with neuropathic agents (e.g. gabapentinoids, antidepressants) where appropriate and referral to the pain service