COVID Era Dr Yeo Sow Nam

• Chairman and founder, Chapter of Pain medicine physicians, Academy of

Pain Management •
Medicine Singapore
Past President , Pain Association of Singapore
• Past President , World institute of pain
• Founder and past head of service , pain management centre and acupuncture
services, Singapore General Hospital
AMS Statement on Pain Procedures during the
COVID-19 pandemic

There is a need to recognize that many patients suffering from pain may deteriorate functionally should pain not be addressed in a timely
and appropriate manner. With the rapidly evolving COVID-19 pandemic situation, there is a need to weigh the risks and benefits of
performing a pain procedure should the patient require it medically[1]. The general aims should be to alleviate severe pain, avoid
significant deterioration of function, avoid unnecessary reliance on opioids or emergency department (ED) visits/ admissions which would
increase risk of exposure to COVID.
Basis for Decision
The decision to postpone or perform a pain procedure must be made in the context of numerous considerations (both medical and
logistical) and individualized to the particular patient’s condition.
• The medical necessity for a given procedure should be established by the pain specialist taking into account the patient’s condition
and prognosis; and the time sensitivity and benefit of the procedure to function and quality of life.
• Factors to consider include
• Severity of pain and its effect on function
• Responsiveness to analgesia and alternative methods of treatment
• Patient’s risk factors for complications from COVID infection
• Risks and benefits of the pain procedure
• Logistical feasibility for performing a given procedure should be determined taking into consideration facility resources (infection
control resources and other equipment, supplies, etc.) and provider and community safety and well-
 COVID Era Pain Management

Justifiable Conditions or Situations

Conditions where interventional procedures could be justified during COVID-19 pandemic include, but not
limited to, the following[2]:
1. ITP or ‘Porta-a-cath’ system refills or interventions for device infection
2. Intractable cancer pain
3. Intractable post-herpetic neuralgia
4. Acute herniated disc and/or worsening lumbar radiculopathy severely limiting function and not candidate
for surgery or has a long waiting time more than 4 weeks for surgery
5. Intractable trigeminal neuralgia
6. Intractable headache conditions
7. Other intractable, medically resistant pain syndromes eg severe neuropathic pain conditions/ complex
regional pain syndrome
 COVID Era Pain Management
Weighing and Mitigating Risks of Steroids
It has been suggested that chronic pain patients may be more susceptible to COVID-19 with the majority of pain patients being elderly with multiple
comorbidities. A statement by Faculty of Pain Medicine of Royal College of Anaesthetists[3] addressed the potential harm of steroids injection to individuals who
may be incubating or later develop COVID-19. However, the uncertain effects or even benefits of anti-inflammatory agents and steroids in COVID-19 remain
unknown. If the avoidance of pain management interventions causes significant deterioration of function and necessitate use of long-term opioids or NSAIDS,
these could also compromise the patient’s immune status. Prolonged use of Opioids and NSAIDS may also pose severe systemic risks to patients. In a recent
published review article, Beth Russell et al[4] found no published evidence for or against the use of NSAIDs and steroids in COVID-19 patients. Meanwhile, there
appeared to be some evidence that corticosteroids may be beneficial if utilised in the early acute phase of infection [5]. However, conflicting evidence from the
World Health Organisation surrounding corticosteroid use in certain viral infections means this evidence is not conclusive. Given the current availability of
literature, caution should be exercised until further evidence emerges surrounding the use of NSAIDs and corticosteroids in COVID-19 patients.
Hence, carefully balancing risks and benefit and engaging patients in the decision-making process, with accurate documentation is advised.
• Consider risk mitigation strategies in high-risk patients if the interventions are unavoidable for medical or humanitarian reasons:
• Consider evaluating risks/benefits of steroid injections and use a decreased dose especially in high-risk patient populations
• Use Dexamethasone (as an alternative to particulate steroids eg triamcinolone) if possible
• Use lowest dose possible
• Stagger injections adequately to reduce drug dose
• Consider non-steroid requiring alternatives whenever possible (e.g. pharmacological strategies, RFA), considering if additional risks if any are justifiable.
Counselling and Consent
Patients should be counselled on the risks and benefits of pain interventions, alternative treatments and the potential increased risk of steroid use but current
lack of clear evidence associated with increased risk of poor outcome with COVID-19 infection,and be engaged in decision making. The discussion and decision
should be clearly documented.
 COVID Era Pain Management

The COVID-19 pandemic is placing severe evolving challenges to our healthcare system. The Chapter
of Pain Medicine Physicians, AMS, Singapore recognises many new challenges, including lack of
multidisciplinary members of pain services, lack of continuity of care for patients crossing different health
cluster and potentially increased risks of pain intervention procedures. However, such procedures are
often medically necessary to avoid worsening medical conditions and unnecessary suffering. Options,
benefits and risks must be individualised and where indicated and benefits outweigh risks, these
procedures should still be considered.

• Eccleston C, Blyth FM, Dear BF, Fisher EA, Keefe FJ, Lynch ME, et al. Managing patients with chronic pain during the COVID-19 outbreak: considerations for the rapid introducti
on of remotely supported (eHealth) pain management services. Pain. 2020;161: 889–893.
• American Society of Regional Anesthesia, Pain Medicine. Recommendations on Chronic Pain Practice during the COVID-19 Pandemic. [cited 30 Mar 2020]. Available:
https://www.asra.com/page/2903/recommendations-on-chronic-pain-practice-during-the-covid-19-pandemic
• FPM-COVID-19-Steroid-Statement-2020.pdf. Available: https://fpm.ac.uk/sites/fpm/files/documents/2020-03/FPM-COVID-19-Steroid-Statement-2020.pdf
• Russell B, Moss C, Rigg A, Van Hemelrijck M. COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting?
Ecancermedicalscience. 2020;14: 1023.
• Russell B, Moss C, George G, Santaolalla
A, Cope A, Papa S, et al. Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence.
Ecancermedicalscience. 2020;14: 1022.
Increased Incidence of Pain?

1. Work from Home

• Lack of activities
• Increased computer and TV duration
• Deconditioning and prolonged sitting
2. Cut in travel. Increased gym and outdoor. Overuse.
3. Stress from lack of work
4. Stress from overwork
 IASP definitions 1994: Neuropathic Pain

Neuropathic pain
Pain initiated or caused by a primary
lesion or dysfunction in the nervous system

Peripheral neuropathic pain Central neuropathic pain

Pain initiated or caused by a primary Pain initiated or caused by a primary
lesion or dysfunction in the lesion or dysfunction in the
peripheral nervous system central nervous system

Merskey H, et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994: 209-12.
IASP modified definitions 2008:
Drafts only, not yet approved!
IASP modified definitions 2008:
Drafts only, not yet approved!
Typical Neuropathic Pain Syndromes

• peripheral neuropathies
• metabolic: diabetic,
• toxic: alcohol, chemotherapy, others
• postinfectious: PHN, HIV, CMV
• posttraumatic
• sciatica
• postoperative
• neuroma or nerve entrapment
• phantom limb pain
• CRPS (Complex Regional Pain Syndrome [RSD])
• spinal cord injury
• post-stroke pain
• MS
Prevalence/incidence of neuropathic pain

Prevalence of neuropathic pain in the general community > 2%

• 20-24% of diabetics experience painful DPN

• 25-50% of patients >50 years with herpes zoster develop PHN
(≥3 months after healing of rash)
• Up to 20% develop post-mastectomy pain
• One-third of cancer patients have neuropathic pain
(alone or with nociceptive pain)
• >50% of low back pain patients have associated neuropathic pain

SPHERE Positive Management of Persistent Pain Algorithms (2006). Schmader KE. Clin J Pain 2002; 18: 350-4. Stevens PE, et al.
Pain 1995; 61: 61-8. Davis MP, Walsh D. Am J Hosp Palliat Care 2004; 21: 137-42. Deyo RA, Weinstein JN. NEJM 2001; 344: 363-70.
Neuropathic pain: underlying mechanisms

Peripheral Mechanisms Central Mechanisms

• Membrane hyperexcitability  Membrane hyperexcitability

 Ectopic discharges  Ectopic discharges
• Peripheral sensitisation  Wind up
 Central sensitisation
 Denervation supersensitvity
 Loss of inhibitory controls

It is important to realise that different mechanisms are responsible

for neuropathic pain in different patients and different causes!

Attal N, et al. Acta Neurol Scand 1999; 173: 12-24. Woolf CJ, et al. Lancet 1999; 353: 1959-64. Roberts MTH, et
al. In Casey KL (Ed). Pain and central nervous system disease. 1991.
Pain Pathways
Mechanisms of neuropathic pain:
peripheral sensitisation

Nerve Growth Factor NGF

Upregulation of vanilloid receptor 1 Heat sensitivity

Lower firing
Upregulation of SNS/PN3 Na channels
+
threshold

Woolf CJ, Salter MW. Science 2000; 288: 1765-68.

Mechanisms of neuropathic pain:
central sensitisation
• Peripheral inputs trigger molecular changes in central
neurones
Reduce effect
Modification of GABA, glycine receptors of inhibition

Lower firing
NMDA and AMPA receptor activation
threshold

• Long-lasting changes may result from

• Deafferentiation hyperactivity
• Loss of large fiber inhibition
• Inhibitory interneuron death

GABA = -aminobutyric acid; NMDA = N-methyl-D-aspartate;

AMPA = -amino-3-hydroxyl-5-methyl-4-isoxazolepropionate.
Woolf CJ, Salter MW. Science 2000; 288: 1765-68.
Mismatch between stimulus and response
(homosynaptic sensitization)

disruption of the normal specialisation of the somatosensory system

aberrant convergence (heterosynaptic sensitization)

18
Glia and Central Sensitisation
 Glia and
Central Sensitisation

Gao&Ji
20 Pharmacol Ther 2010;126:56
Cortical Reorganisation in Central Sensitisation

At admission After 12 weeks functional treatment

Most Patients Currently Receive Rx Medications for
Neuropathic Pain
Almost all patients were receiving Rx meds for their neuropathic pain
Polypharmacy for Pain is Prevalent in PHN
Five; 9%

Four; 6%

Three;
12% Polypharmacy
One; 44% =56%

Two; 29%

(N=196)
Current Prescription Medication Use Among Patients
Treated for Neuropathic Pain
Neuropathic Pain: The Challenge Summary

• Neuropathic prevalence may be under-reported

• Diagnosis can be challenging for physicians
• GPs are most challenged, yet they are pivotal in the management of neuropathic pain
• Comorbid conditions are prevalent
• Signs and symptoms of anxiety, depression, sleep disturbance
• Neuropathic pain is associated with significant quality of life and functional
impairment
• Current treatment is suboptimal
• Evidence-based treatments (e.g. AEDs, TCAs) not always prescribed
• Some patients do not respond to AEDs and TCAs
 Pharmacological Therapy

Anti-
depressants

Anti-
Opioids
convulsives

27
 Neuropathic Pain: Pharmacology

• Antidepressants • Opioids
• Tricyclic antidepressants • Morphine
• SSRI • Oxycodone
• SNRI • Tramadol
• Anticonvulsants • NMDA antagonists
• Gabapentin • Memantine
• Pregabalin • Amantadine
• Valproic acid • Dextromethorphan
• Topiramate • Cannabinoids
• Carbamazepine • Topicals
• Oxcarbazepine • Lidocaine
• Phenytoine • Capsaicin
• Lamotrigine • Other
• Levetiracetam
• Botulinum toxin
Neuropathic Pain: Anticonvulsants Status

Pain conditions: Gabapentin

Painful diabetic neuropathy Pregabalin

Lamotrigine
Painful neuropathy
Phenytoin
HIV neuropathy Carbamazepine
Guillain-Barré syndrome Oxcarbazepine
Postherpetic neuralgia Valproic acid
Tiagabine
Trigeminal neuralgia
Felbamate
Central poststroke pain Topiramate
Central spinal cord injury pain Benzodiazepines
Mixed neuropathic pain
 Pharmacological management of NP: Step 1

• Assess pain Diagnosis of NP

• Treat cause of pain
• Identify relevant comorbidities
• Explain diagnosis treatment plan and
expectations

Dworkin et al. 2007

 Pharmacological management of NP: Step 2

• Start therapy of the underlying NP disease

• Start therapy with compound:
• Sec. amine TCA or SSNRI
• A Ca++α2δ-binding agent
• Local peripheral NP: topical lidocaine
• For a few conditions: an opioid
analgesic
• Consider non-pharmacological therapies as
an adjunct

Dworkin et al. 2007

 Pharmacological management of NP: Step 3

• Reassess pain and quality of life

frequently
• If substantial pain relief (pain<3) and side
effects are tolerable: continue treatement
• If partial pain relief (pain>4) add one other
first line treatment
• If no or insufficient pain relief (<30%
reduction) switch to other first line
treatment)

Dworkin et al. 2007

 Pharmacological management of NP: Step 4

• If first line treatments alone or in combination

fail, consider 2nd or 3rd line medications:
• carbamazepine, oxcarbazepine,
topiramate, valproic acid, NMDA
anatagonists, topical capsaicin, SSRI,
bupropion

Dworkin et al. 2007

Treatment of Neuropathic Pain:
Sodium Channel Blockade
Treatment of Neuropathic Pain:
NMDA Receptor Antagonists
Treatment of Neuropathic Pain:
Calcium Channel Modulation
Treatment of Neuropathic Pain:
Enhancing Descending Inhibition
 Gilron et al.
38 CMAJ 2006;175(3):265
Conclusion

• Neuropathic pain is a common problem

• Neuropathic pain can often be diagnosed by a good history and
basic examination
• Neuropathic pain is unresponsive to many analgesics effective in
nociceptive pain
• Neuropathic pain requires commonly use of co-analgesics such
as antidepressants and anticonvulsants
PRECISION
Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen
NISSEN SE ET AL,NEJM 2016

Objective To assess CV, GI, renal, and other outcomes with celecoxib as compared to two ns-NSAIDs

Primary composite: First occurrence of adjudicated APTC event (cardiovascular death

[including hemorrhagic death], nonfatal myocardial infarction, or nonfatal stroke)
Endpoints
Secondary composite: Major adverse CV events (primary endpoint + coronary revascularization or
hospitalization for unstable angina or transient ischemic attack)
Secondary: Clinically significant GI events

Design Randomized, multicenter, double-blind, non-inferiority trial

Population 24,081 OA or RA patients ≥18 years who required daily NSAID treatment for arthritis pain, with or at
increased risk for CV disease

Celecoxib 100–200 mg BID

Randomized treatments Ibuprofen 600–800 mg TID
Naproxen 375–500 mg BID
Esomeprazole 20–40 mg was provided to all patients for gastroprotection

Treatment duration Minimum follow-up: 18 months

APTC: Antiplatelet Trialists’ Collaboration; BID: twice daily; CV: cardiovascular; GI: gastrointestinal; ns-NSAID: non-selective non-steroidal anti-inflammatory drug; OA: osteoarthritis; RA: rheumatoid arthritis; TID: three times daily.
Reference: 1. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519–2529. doi:10.1056/NEJMoa1611593.
PRECISION
Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen
NISSEN SE ET AL,NEJM 2016

Similar incidence of CV events compared to naproxen or ibuprofen 1

Time to APTC event, intent-to-treat population* Time to APTC event, on-treatment population*
Number of patients Number of patients
HR (95% CI) with APTC event HR (95% CI)NI
with APTC event
NI (%) Celecoxib vs. Ibuprofen 0.81 (0.65, 1.02) (%)
In the landmark PRECISION study, celecoxib
Patients with APTC event (%)

Celecoxib vs. Ibuprofen 0.85 (0.70, 1.04) p<0.001 p<0.001

Celecoxib vs. Naproxen 0.93 (0.76, 1.13) p<0.001
Ibuprofen vs. Naproxen 1.08 (0.90, 1.31) p=0.02
Celecoxib vs. Naproxen 0.90 (0.71, 1.15)
p<0.001 100–200 mg BID demonstrated a similar
Ibuprofen vs. Naproxen 1.12 (0.89, 1.40)
p=0.025 incidence of CV events compared to naproxen
375–500 mg BID or ibuprofen 600–800 mg TID

PRECISION enrolled over 24,000 OA or RA

patients with or at increased risk for CV disease 1
Months since randomization Months since randomization

Celecoxib 100–200 mg BID Naproxen 375–500 mg BID Ibuprofen 600–800 mg TID

(mean daily dose: 209 mg) (mean daily dose: 852 mg) (mean daily dose: 2,045 mg) Adapted from Nissen SE, et al.

APTC: Antiplatelet Trialists Collaboration; BID: twice daily; CV: cardiovascular; HR: hazard ratio; NI: non-inferiority; NSAID: non-steroidal anti-inflammatory drug; OA: osteoarthritis;
RA: rheumatoid arthritis; TID: three times daily.
* PRECISION was a randomized, double-blind, parallel-group, non-inferiority study evaluating the cardiovascular safety of celecoxib and prescription strength naproxen or ibuprofen in
24,081 osteoarthritis or rheumatoid arthritis patients with or at increased risk for cardiovascular disease, who required daily NSAID treatment to maintain their quality of life. The primary endpoint (adjudicated) was
the first occurrence of an APTC endpoint, defined as a composite of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke.
The protocol pre-specified a minimum follow-up time of 18 months, with censoring of data from event-free patients after 30 months in the intention-to-treat population and after 43 months in the on-treatment
population.
Reference: 1. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519–2529. doi:10.1056/NEJMoa1611593.
PRECISION-ABPM
Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or
Naproxen Ambulatory Blood Pressure Measurement

Objective To assess the differential effects on ambulatory BP of celecoxib vs. naproxen and ibuprofen

Primary: Change from baseline in mean 24-hour SBP at Month 4

Endpoints An additional post hoc analysis was conducted for treatment comparison of the percent
of normotensive patients who became hypertensive at Month 4*

Design A predefined sub study of PRECISION

Population 444 OA or RA patients ≥18 years who required daily NSAID treatment for arthritis pain,
with or at increased risk for CV disease

Celecoxib 100–200 mg BID

Randomized treatments Ibuprofen 600–800 mg TID
Naproxen 375–500 mg BID
Esomeprazole 20–40 mg was provided to all patients for gastroprotection

Treatment duration 4 months

BID: twice daily; BP: blood pressure; CV: cardiovascular; DBP: diastolic blood pressure; NSAIDs: non-steroidal anti-inflammatory drugs; OA: osteoarthritis; RA: rheumatoid arthritis; SBP: systolic blood pressure; TID: three times daily.
* Normotensive patients were defined as those with baseline 24-hour SBP <130 mmHg and DBP <80 mmHg. Hypertensive patients were defined as those with mean 24-hourSBP ≥130 mmHg and DBP ≥80 mmHg at month 4.
Reference: 1. Ruschitzka F, Borer JS, Krum H, et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis:
the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial . Eur Heart J. 2017;38(44):3282–3292. doi:10.1093/eurheartj/ehx508.
PRECISION-ABPM
Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or
Naproxen Ambulatory Blood Pressure Measurement

Effect on systolic blood pressure at month 41*

-1.8 mmHg
(95% CI -4.15, 0.47)
p=0.12
-3.9 mmHg -2.1 mmHg
LSM change in 24-hour

4 (95% CI -6.19, -1.61) (95% CI -4.36, 0.23)

ambulatory SBP at

p≤0.001 p=0.08
month 4 (mmHg)

3 3.7 p<0.001 In the 4-month PRECISION-ABPM trial,

celecoxib 100–200 mg BID demonstrated a
2
significantly smaller change in 24-hour mean
1 1.6 SBP vs. ibuprofen 600–800 mg TID 1*
p=0.117

-1

Celecoxib
- Ibuprofen Naproxen
100–200
0.3mg BID
p=0.801 600–800 mg TID 375–500 mg BID
(n=146) (n=151) (n=147)

Adapted from Ruschitzka F, et al.

Results were not significantly different for celecoxib vs. naproxen and ibuprofen vs. naproxen.1

BID: twice daily; CI: confidence interval; LSM: least squares mean; NSAID: non-steroidal anti-inflammatory drug; SBP: systolic blood pressure; TID: three times daily.
* PRECISION-ABPM (Ambulatory Blood Pressure Measurement) was a pre-specified substudy of PRECISION, a randomized, multicenter, double-blind, non-inferiority trial involving osteoarthritis
or rheumatoid arthritis patients with or at increased risk for cardiovascular disease. Patients ≥18 years of age who required daily treatment with NSAIDs for arthritis pain (as determined by the patient and physician) were randomized 1:1:1 to
receive either celecoxib 100–200 mg BID, ibuprofen 600–800 mg TID, or naproxen 375–500 mg BID with matching placebos for 4 months.
Esomeprazole 20–40 mg was provided for gastric protection.
Reference: 1. Ruschitzka F, Borer JS, Krum H, et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated
Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial. Eur Heart J. 2017;38(44):3282–3292. doi: 10.1093/eurheartj/ehx508.
Other Treatment Modalities

• Neural blockade
• Sympathetic nerve block
• Somatic nerve block
• Physical therapies
• Relaxation therapies
• Cognitive-behavioural therapy
• Neuromodulation
• TENS
• Spinal cord stimulation
• Intrathecal medication
• Neurodestructive techniques
• DREZ lesioning
Opioid Efficacy Studies in Neuropathic Pain
Disorders

• Nonmalignant neuropathic pain disorders

• IV fentanyl
• Postherpetic neuralgia
• IV morphine
• Controlled-release oxycodone
• Phantom limb pain
• Oral morphine
• Diabetic neuropathy
• Tramadol
• Ocycodone
 Pain Management Guidelines

46
Neuropathic pain screening questionnaire:
ID pain Total Score

-1 = Neuropathic pain not likely

0 = Neuropathic pain less likely
1 = Neuropathic pain less likely
2 = Consider neuropathic pain
3 = Consider neuropathic pain
4 = Strongly consider neuropathic pain
5 = Strongly consider neuropathic pain
 NEUROPATHIC PAIN SYMPATHETIC NERVOUS
SYSTEM CONTRIBUTION

TRICYCLIC ANTIDEPRESSANTS - SYMPATHETIC BLOCKS

NORTRIPTYLINE/AMITRIPTYLINE

Topical medication
α2δ ligands /Lamotrigine
TENS
Psychological management
Physical activation

KETAMINE INFUSION
LOCAL ANAESTHETIC
BLOCKS / INFUSIONS

TRIAL OPIOIDS

TRAMADOL STRONG OPIOIDS

CONSIDER INVASIVE THERAPY

SPINAL CORD STIMULATION Cognitive Behavioural
SPINAL ANALGESIC THERAPY Therapy
Persistent postsurgical pain is a common but under-
recognized problem
Estimated Estimated Estimated US
incidence of incidence of surgical volumes
persistent severe (disabling) (1000s)
postsurgical pain pain

Inguinal hernia repair 10% 2–4% 600

Lower limb amputation 30–50% 5–10% 160
Breast surgery 20–30% 5–10% 480
(lumpectomy or
mastectomy)
Thoracotomy 30–40% 10% 200
Total knee arthroplasty 12% 2–4% 550
Coronary artery bypass 30–50% 5–10% 598
surgery
Caesarean section 10% 4% 220

1. Kehlet H, et al. Lancet 2006;367:1618-1625;

2. Durkin B, et al. Expert Opin Pharmacother 2010;11:2751-2758.
Risk factors for development of persistent
postsurgical pain

1. Genetic susceptibility
2. Moderate to severe preoperative pain
3. Psychosocial factors
4. Age and sex
5. Surgical approach with risk of nerve damage
6. Poorly controlled postoperative pain

1. Kehlet H, et al. Lancet 2006;367:1618-1625;

2. Durkin B, et al. Expert Opin Pharmacother 2010;11:2751-2758;
3. Schug SA, Pogatzki-Kahn EM. Pain: Clinical Updates 2011;19:1-5.
Most relevant risk factor:
Severity of acute postoperative pain

• The severity of acute postoperative pain is closely

correlated with the development of persistent
postsurgical pain
• It has yet to been established if the relationship is
one of causality or association
• Does treating acute pain prevent persistent pain?
• Do patients with acute postoperative pain really
have ongoing preoperative pain?
• Do central neuroplastic changes induce both
acute pain and persistent pain independently?

Schug SA, Pogatzki-Kahn EM. Pain: Clinical Updates 2011;19:1-5.

Persistent postsurgical pain:
Potential for prevention

• Avoidance of intraoperative nerve injury1

• Careful dissection
• Reduction of inflammatory responses
• Use of minimally invasive surgical techniques
• Aggressive multimodal analgesia1
• Afferent blockade, COX-2 inhibitors and opiates to
alleviate inflammatory pain, and anti-neuropathic pain
agents to alleviate neuropathic pain1
• Initiated in the pre-op period and extended into the
post-op period (preventive analgesia)2
1. Kehlet H, et al. Lancet 2006;367:1618-1625;
2. Pogatzki-Kahn EM, Zahn PK. Curr Opin Anaesthesiol 2006;19:551-555.
Pregabalin and gabapentin are believed to impact
central sensitization
• Binds with high affinity to the α2δ Pregabalin and gabapentin reduce
excessive neurotransmitter release
subunit of voltage-gated calcium
channels at the dorsal horn and dorsal
root ganglia Presynaptic PREGABALIN
α2δ subunit

• Reduces excessive calcium-dependent Ca2+ channel

release of substance P and glutamate

• Although the exact mechanism of Ca2+ ion
Neurotransmitters
action of pregabalin and gabapentin in (eg, substance P,
glutamate)

humans is unknown, results from

Postsynaptic
animal models suggest that binding to
the α2δ subunit may be associated with
their anti-hyperalgesic and anti-
allodynic effects
1. Costigan M, et al. In: Siegel GJ, et al, eds. Basic Neurochemistry: Molecular,
Cellular and Medical Aspects. 7th ed. Burlington, MA: Elsevier Academic Press;2006:927–938;
2. Field MJ, et al. Proc Natl Acad Sci USA 2006;103:17537-17542.
Pregabalin: Effective in surgical neuropathic pain in a range
of orthopaedic surgical procedures and post-trauma

Study Population Intervention Outcome

van Seventer Patients with post- Pregabalin 150–600 Reduction in pain
(2010) traumatic peripheral mg versus placebo intensity, and improved
neuropathic pain, sleep and overall patient
including status
postsurgical pain
(n=254)

Spreng (2011) Patients undergoing Pregabalin 150 mg Reduction in pain

elective lumbar 1 hour pre-op versus intensity at rest, opioid
micro-discectomy placebo consumption, and pre-op
(n=50) anxiety

Kim JC (2011) Patients for elective Pregabalin 75 or 150 Reduction in opioid

posterior lumbar mg 1 hour pre-op, then consumption and use of
spinal fusion (n=84) 12 hours post-op, pain rescues with 150 mg
versus placebo dose
Pregabalin: Effective in surgical neuropathic pain in a range
of orthopaedic surgical procedures and post-trauma (cont’d)

Study Population Intervention Outcome

Buvanendran Patients with knee Pregabalin 300 mg 1 hour Reduction in
(2010) osteoarthritis for pre-op, then 50–150 mg incidence of chronic
elective total knee twice daily for 14 days, pain at 3 months and
arthroplasty (n=240) versus placebo 6 months post-op

Burke (2010) Patients with Pregabalin 300 mg 90 mins Reduction in pain

chronic lumbar pre-op, then 150 mg at 12 intensity and
sacral radiculopathy and 24 hours post-op, improved functional
for elective lumbar versus placebo outcomes at 3
discectomy (n=40) months post-op
Meta-analysis: Pregabalin administration reduces the
amount of post-op analgesic drugs
STUDY/SUBGROUP HEDGES’ G SE WEIGHT HEDGES’ G
IV, RANDOM, 95% CI
50–150 mg/day
Agarwal -1.776 0.313 15.6% -1.78 (-2.39, -1.16)

Jokela laparo 75 -0.245 0.26 16.4% -0.24 (-0.75, 0.26)

Schulmeyer -1.3 0.244 16.6% -1.30 (-1.78, -0.82)

Subtotal (95% CI) 48.6% -1.10 (-1.96, -0.23)

225–300 mg/day
Ittichaikulthol -2.12 0.281 16.1% -2.12 (-2.67, -1.57)

Kim thyroidectomy -0.258 0.205 17.2% -0.26 (-0.66, 0.14)

Lavand’homme -0.348 0.104 18.2% -0.35 (-0.55, -0.14)

Subtotal (95% CI) 51.4% -0.88 (-1.79, 0.04)

Total (95% CI) 100.0% -0.98 (-1.58, -0.38)

-4 -2 0 2 4

Favors experimental Favors control

Engelman E, Cateloy F. Acta Anesthesiol Scand 2011;55:927-943.

 PRECISION
NISSEN SE ET AL,NEJM 2016

Prospective Randomized Evaluation of CelecoxibIntegrated Safety vs.

Ibuprofen Or Naproxen (PRECISION), 24081 patients

Similar rates of cardiovascular risk in patients treated with prescription

doses of celecoxib, ibuprofen and naproxen who had a clinical diagnosis
of osteoarthritis (OA) or rheumatoid arthritis (RA), were at high risk for
cardiovascular disease, and required daily treatment with non-steroidal
anti-inflammatory drugs (NSAIDs) to control symptoms of arthritis.

with celecoxib experienced significantly fewer gastrointestinal events as

compared with those receiving prescription doses of ibuprofen or
naproxen.

refute the assumption held by many physicians that naproxen treatment

results in better cardiovascular outcomes as compared to other NSAIDs,
including celecoxib.
Advanced Interventional Pain Management
Layering of Contrast in Epidural Space (C5-
6 Epidural)
Epidural Adhesiolysis and Neuroplasty
Implantable Stimulator
 Indications for SCS

• Arachnoiditis • Peripheral
• Failed Back Syndrome Neuropathies
• Radiculopathy • CRPS Types I & II
• Plexus Lesions • Spinal Cord Injury
• Ischemic Limb Pain • Angina Pectoris
• Phantom Limb Pain • Multiple Sclerosis
 SCS: Reduction in Pain

Study No. of patients Mean Follow-up Outcome

North 171 7 years 52% with ≥ 50% relief
Pain 1993
Turner 39 studies: meta- 16 months 59% with ≥ 50% relief
Neurosurgery 1995 analysis
De La Porte 64 4 years 55% good to
Pain 1993 excellent relief
Segal 24 19 months 78% good to very
Neurol Research good relief
1998
Kumar 189 5.6 years 59% good to
Surg Neurol 1998 excellent relief
Burchiel 70 1 year 55% with ≥ 50% relief
Spine 1996
 PROCESS Study

• 100 FBSS patients with predominant radicular leg pain

• Randomised to SCS plus CMM or CMM alone
• Primary outcome
• Number of patients with ≥50% leg pain relief at 6 months
• Secondary outcomes evaluated at 1, 3, 6, 9, 12, 18 and 24
months
• Pain relief (leg and axial back VAS)
• Quality of life (SF-36 and EQ-5D)
• Function (Oswestry Disability Index)
• Patient satisfaction
• Need for drug or non-drug therapy for pain
• Time away from work
• Adverse events
• Crossover after the 6-month visit was permitted

Kumar K, et al. Pain 2007;132:179-188

73
 Ziconotide
• FDA approved in 2004: chronic intractable pain

• 1000 times stronger than morphine as analgesic

Conus Magus
 Vasomotor changes

*same patient, don’t ask…

Edema: factors/clusters with sudomotor
Sudomotor changes
Extreme Trophic Changes
 IT Ziconotide (Rauck 2006)

• Randomised, double-blind placebo-controlled

trial
• Chronic refractory non-cancer pain
• Ziconotide (n=112), Placebo (n=108)
• IT infusion at 0.1 mcg/h, increasing gradually
(0.05-0.1 mcg/h increments) over 3 weeks

Rauck RL, Wallace MS, Leong MS, et al. J Pain Symptom Manage 2006;31:393-406
Rauck RL, Wallace MS, Leong MS, et al. J Pain Symptom Manage 2006;31:393-406
Ziconotide as alternate Rx – case report

•17 y/o female, CRPS for 5 years

•atrophic features
•Severe allodynia
•Could not bear weight
•Failed PT, medical and cont. RA
•Responded to SCS trial
•Exacerbated after removal
•implanted
•Re injury – lost SCS efficacy
•Slow Prialt trial (6 wks) - 24 mcg/day
 Ziconotide – case report

•Skin changes almost gone

•Started college this year
•Uses SCS for burning dysesthesia
 Summary

• Chronic neuropathic pain is a disease, not a symptom

• “Rational” polypharmacy is often necessary
• Treatment goals include
• Balancing efficacy, safety, and tolerability
• Reducing baseline pain and pain exacerbations
• Improving function and QOL
• Adequate Acute Pain Management reduces risk of
chronic pain
• Current guidelines for neuropathic pain management
involve novel agents and interventions
 Thank You

alexyeosn@gmail.com