Persistent Postsurgical Pain:

Risk Factors and Prevention

Division of Pain Medicine

Department of Anesthesiology
University Hospitals of
Cleveland

Salim Hayek, MD,

PhD
Persistent Postsurgical Pain:
Risk Factors and Prevention
Salim M. Hayek, MD, PhD

Division of Pain Medicine

Department of Anesthesiology
University Hospitals of Cleveland
 Conflicts of Interest

None Relevant
Persistent Postoperative Pain
 Learning Objectives
Physiology & Pathophysiology of Pain
Nociceptive vs. Neuropathic Pain
Predictors of Chronic Postsurgical Pain
Targets for Prevention of Persistent
Postsurgical Pain
 Postoperative Pain
Pain Score
PPP

0 1 2 3 4 5 6 180

POD
Persistent Postsurgical Pain (PPP) = Pain >
3-6 mo after surgery
 PPP--Incidence

Compares in its scale to morbidity of other forms of neuropathic

pain such as post-herpetic neuralgia and post-stroke pain (5-10%)
Kehlet H et al., Lancet. 2006 May 13;367:1618-25
 PPP
A significant problem
Etiologies
Ongoing Inflammation
Neuropathic Pain: surgical
injury to peripheral nerves
Drug seeking/psychogenic
 Immediate Post-op
Around-the-Clock Breakthrough Pain
Medication

Activation of
nociceptors
Inflammation
~ injury to nerves

Most patients respond well to opiates and COX inhibitors.

If nerves are injured during surgery, a neuropathic
component of the pain might develop immediately and then
persist in the absence of any peripheral noxious stimulus
or ongoing peripheral inflammation
 PAIN = 2 subtypes
Pain: nociceptive or neuropathic
Nociceptive: tissue insultnociceptor
activation
Neuropathic: pathological lesion or
dysfunction of the nervous system
Neuropathic pain treatment
differs from that of nociceptive
pain
 Inflammatory Pain
The phenomena, although evoked within a
matter of minutes, outlast the precipitating
tissue injury for several hours or days
However, they are generally reversible
 Inflammatory pain is the pain that, in the
absence of any peripheral nerve damage,
drives acute postoperative pain until the
surgical wound has healed
If a focus of ongoing inflammation persists,
however, so will the pain
Kehlet H et al., Lancet. 2006 May 13;367:1618-25
 Neuropathic Pain
Occurs as a result of a primary lesion
or dysfunction in the nervous system
Key feature: combination of sensory
loss with paradoxical hypersensitivity
 spontaneous pain, dysesthesia,
hypersensitivity, including allodynia
and hyperalgesia and hyperpathia

Kehlet H et al., Lancet. 2006 May 13;367:1618-25

 Surgical nerve injury  PPP

Postsurgical chronic pain closely resembles

neuropathic pain in most patients
Major nerves trespass the surgical field
of most of the surgical procedures
associated with chronic pain, and damage
to these nerves is probably a prerequisite
for the development of postsurgical
chronic pain
Jung BF et al., Pain 2003; 104: 1-13
Rasmussen PV et al., Pain 2004; 110: 461-469
 Inflammatory vs. Neuropathic

In a subset of patients, a continuous

inflammatory response, such as after
inguinal mesh hernia repair, can contribute
to a maintained inflammatory pain
Differentiation of neuropathic from non-
neuropathic causes of postsurgical pain is
essential

Aasvang E & Kehlet H. Br J Anaesth 2005; 95: 69-76

Inflammatory vs. Neuropathic

Kehlet H et al., Lancet. 2006 May 13;367:1618-25

Neuropathic Pain following Surgery
Signs of neurological damage, in the form
of hypoesthesia
mastectomy
hernia repair
mandibular osteotomy
Use of a rib retractor blocks intercostal
nerve conduction by 50–100% (EMG)
degree of nerve damage correlates with
intensity of chronic pain

Rogers ML, Eur J Cardiothorac Surg 2002; 21: 298-301

Benedetti F, Thorac Cardiovasc Surg 1998; 115: 841-847
 Neuronal Plasticity & Pain
2 kinds of plasticity:
Reversible changes in the “software” of the
system, operates during inflammatory pain
After nerve injury, the “hardware” itself is
altered
no simple continuum from acute to
chronic pain that correlates with the
duration or intensity of peripheral injury

Kehlet H et al., Lancet. 2006 May 13;367:1618-25

 Neuropathic Pain Changes
Up regulation of α2δ subunit of Ca2+ Ch
Neuroimmune sequelae  ↑pain sensitivity
Degeneration of nerve cut end/infl. cells
Release of TNF-α signaling molecules
Microglia are activated in the spinal cord
Interruption of nerve contact with target
small unmyelinated neurons death (excitotoxic)
inhibitory interneurons death
even cortical changes in gray mater
 PPP
Etiologies
Ongoing Inflammation
Neuropathic Pain: surgical
injury to peripheral nerves
Drug seeking/psychogenic
 PPP--Risk Factors
Nerve Injury
Genetic Susceptibility
Preceding Pain
Psychosocial Factors
Age & Sex

Kehlet H et al., Lancet. 2006 May 13;367:1618-25

 Nerve Injury
Seems to be necessary--in most cases
Most patients with post-surgical
nerve damage no pain
Severe nerve damage after mandibular
osteotomy  neuropathic pain only in 10%
Nerve damage alone: Not sufficient
for the development of PPP

Mikkelsen T et al., Anesth Analg. 2004 Jul;99(1):146-51

Jaaskelainen SK et al., Neurology. 2004 Jun 8;62(11):1951-7
 Genetic Susceptibility
Inconsistent pain response likely heritable
Generation of pain
Experience of pain
Response to analgesics
Rats: Susceptibility to neuropathic pain
Clinical evidence
High COMT activity  TMJ pain
Melanocortin-1 receptor gene (associated with
red hair/fair skin)  greater female specific κ-
opioid analgesia
 Preceding Pain
Correlates with development of PPP
Severe pre-amputation pain α phantom
limb pain1
Intensity of acute post-operative pain
correlates with PPP following
Breast surgery2
Thoracotomy3
Inguinal herniorrhaphy4

1. Nikolajsen L et al., Lancet. 1997 Nov 8;350(9088):1353-7

2. Tasmuth T et al., Pain. 1996 Dec;68(2-3):343-7
3. Katz J et al., Clin J Pain. 1996 Mar;12(1):50-5
4. Callesen T et al., Br J Surg. 1999 Dec;86(12):1528-31
 Psychosocial Factors
Modulators of the pain response
Expectation of post-op pain
Fear of post-operative pain
Pre-operative anxiety
Past memories
Social environment
Work
Levels of physical activity
Catastrophizing
Kehlet H et al., Lancet. 2006 May 13;367:1618-25
 Age & Sex
Older patients undergoing
herniorrhaphy have a lower
risk for developing PPP than
young patients
Women have more
postoperative pain than men
Poobalan AS et al., Clin J Pain. 2003 Jan-Feb;19(1):48-54
Katz J et al., Pain. 2005 Dec 15;119(1-3):16-25
 Prevention Strategies
Surgical Technique

Avoid intraoperative nerve injury

Careful dissection
↓ inflammatory responses
Use minimally invasive techniques

Kehlet H et al., Lancet. 2006 May 13;367:1618-25

 Prevention Strategies
Surgical Technique
Herniorrhaphy
Laparoscopic technique can ↓ risk of nerve
damage
Light weight mesh  ~less inflammation
Mastectomy
Preservation of intercostal brachial nerve could
decrease chronic pain
Increased use of sentinel lymph node biopsy
might ↓ ALND
Thoracic Surgery
Thoracoscopic techniques >> rib retractors
Intracostal suture / muscle sparing
Grant AM et al., Br J Surg. 2004 Dec;91(12):1570-4
Macrae WA, Br J Anaesth. 2001 Jul;87(1):88-98
 Pre-emptive Analgesia
Clinical data: unfavorable in general
Most trials have used
Local anesthetics
Opioids
COX inhibitors
Nerve injury is the major factor in PPP
Additional promising agents include:
NMDA antagonists, gabapentin or pregabalin,
venlafaxin or duloxetine, TNF-α blockers…

Nikolajsen L et al., Lancet. 1997 Nov 8;350(9088):1353-7

Kehlet H et al., Lancet. 2006 May 13;367:1618-25
 SNRI
Antidepressants

NMDA blockers

Neurogenic soup
blockers
 Future Therapies
 Administration of growth factors, such as glial cell
line-derived neurotrophic factor (GDNF), could
prevent injury-induced transcriptional changes in
sensory neurons
 Prevention of microglial activation: minocycline
 Prevent apoptosis in the DRG or dorsal horn
 Pharmacological targets might include blockade of
 Nav1.3, Nav1.7, and Nav1.8 sodium channels
 potassium channel openers in sensory neurons
 P2X4 and P2X7 purinergic receptor antagonists in microglia
 use-dependent N-type calcium channel
 α2δ binding drugs
 glutamate transporters and inhibit caspases to decrease
excitotoxicity