Multimodal pharmacotherapy with

Celecoxib and Pregabalin

1
 Nociceptive Pain
Somatic Visceral

Trauma

Musculoskeletal injury Ischemic, e.g., myocardial Abdominal colic

infarction

Post-operative pain

Burn pain
Infection, e.g.,
pharyngitis
Dysmenorrhea
Fishman SM et al (eds). Bonica’s Management of Pain. 4th ed. Lippincott, Williams and Wilkins; Philadelphia, PA: 2010.
 Neuropathic Pain

Post-stroke pain Postherpetic neuralgia

Diabetic peripheral neuropathy

Common descriptors
Shooting
Electric shock-like
Burning
Tingling
Numbness Chronic post-surgical pain
Lumbar radicular pain

1. Baron R et al. Lancet Neurol 2010; 9(8):807-19.

 Universe of Pain

Central sensitization/
dysfunctional pain

Multiple pain
Nociceptive pain mechanisms
Neuropathic pain
- Somatic may coexist - Peripheral
- Visceral (mixed pain) - Central

Freynhagen R, Baron R. Curr Pain Headache Rep 2009; 13(3):185-90; Jensen TS et al. Pain 2011; 152(10):2204-5;
Julius D et al. In: McMahon SB, Koltzenburg M (eds). Wall and Melzack’s Textbook of Pain. 5th ed. Elsevier; London, UK: 2006;
Ross E. Expert Opin Pharmacother 2001; 2(1):1529-30; Webster LR. Am J Manag Care 2008; 14(5 Suppl 1):S116-22; Woolf CJ. Pain 2011; 152(3 Suppl):S2-15.
 Algorithm for Treatment of
Acute Pain Based on Severity
Acute pain due to: Mild or moderate
• Sport injury Severe acute pain
acute pain
• Traumatic or
inflammatory condition Inadequate
• Musculoskeletal injury analgesia

Step 1: acetaminophen
(4 g/day maximum dose;
4 h minimum interval between each 1 g dose)
Inadequate
analgesia
Step 2: coxib or nsNSAID
(make choice based on patient risk profile)
Inadequate
analgesia
Topical nsNSAID Step 3: add 1 of following:
Opioids
(with or without combined • Acetaminophen/codeine
(refer patient to pain clinic
oral acetaminophen, • Acetaminophen/tramadol
or specialist)
coxib or nsNSAID) • Tramadol
Coxib = COX-2 inhibitor; nsNSAID = non-specific non-steroidal anti-inflammatory drug
Ayad AE et al. J Int Med Red 2011; 39(4):1123-41.
 Synergistic or Additive Effects of Analgesics
Used Together
• Agents with different mechanisms of action
can potentially have additive or
synergistic effects:
– Acetaminophen/NSAIDS + opioids
– Opioids + local anesthetics
– Centrally acting agents + NSAIDS
– Opioids + 2δ ligands (e.g., dexamethatomidine)

NSAID = non-steroidal anti-inflammatory drug

Bader P et al. Guidelines on Pain Management. European Association of Urology; Arnhem, The Netherlands: 2010;
Kehlet H et al. Acta Anaesthesiol Scand 2010; 55(7):778-84; Paul S et al. Ceylon Med J 2010; 55(4):111-5; Robert B et al. J Pain 2010; 11(8):701-9;
Starks I et al. ISRN Anesthesiology 2011; 2011:742927; Vadivelu N et al. Yale J Biol Med 2010; 83(1):11-25.
 American Society of Anesthesiologists Task
Force on Acute Pain Management Recommendations

• Advocate the use of multimodal analgesia

• “Unless contraindicated, all patients should
receive around-the-clock regimen of NSAIDs,
COX-2 inhibitors, or acetaminophen”

NSAID = non-steroidal anti-inflammatory drug

American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2004; 100(6):1573-81.
 How do nsNSAIDs/coxibs work?
Arachidonic acid

Coxibs : COX-2 (induced by

COX-1 (constitutive) - Celecoxib
- Etoricoxib inflammatory stimuli)
- Parecoxib

Coxibs BLOCK

BLOCK nsNSAIDs BLOCK

nsNSAIDs:
- Diclofenac
Prostaglandins - Ibuprofen Prostaglandins
- Naproxen

Gastrointestinal
cytoprotection, Inflammation, pain, fever
platelet activity

Coxib = COX-2-specific inhibitor; NSAID = non-steroidal anti-inflammatory drug Pain relief

nsNSAID = non-specific non-steroidal anti-inflammatory drug
Gastrosource. Non-steroidal Anti-inflammatory Drug (NSAID)-Associated Upper Gastrointestinal
Side-Effects. Available at: http://www.gastrosource.com/11674565?itemId=11674565.
Accessed: December 4, 2010; Vane JR, Botting RM. Inflamm Res 1995;44(1):1-10.
NSAIDS vs COX-2 Inhibitors
COX-2 Inhibitors
• Inhibits COX-2
• Inhibition of COX-2 has
improved the safety
profile
• Inhibition of COX-2
directly implicated in
inflammation

NSAIDS
• Inhibits both, COX-1 and
COX-2
• Inhibition of COX-1 may
lead to adverse events
• Inhibition of COX-1 has
been related to GI
adverse events

Harirforoosh S, Jamali F. Renal adverse effects of nonsteroidal anti-inflammatory drugs. Expert opinion on drug safety. 2009 Nov 1;8(6):669-81.
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. New England Journal of Medicine. 2001 Aug 9;345(6):433-42. 11
EFFICACY OF CELECOXIB
 Molecular differences between coxib – Oxidative activity

Sulfonamide Sulfone

Sulfones seem to have pro-oxidative activity, not found in sulfonamides:

Sulfone COX-2 inhibitors increase the susceptibility of biological lipids such as LDL to
oxidative modification through a non-enzymatic process, whereas celecoxib had no
significant effect on LDL oxidation rates.
Walter M at el. Atherosclerosis 177 (2004) 235–243
 Change from baseline for average Systolic and Diastolic Blood pressure on day 14 in Elderly
subjects treated with Etoricoxib 90 mg qd, Celecoxib 200 mg bid, Naproxen 500 mg bid, or
Placebo 26
Average ambulatory systolic BP over a 24-hour period between days 1-14
9
7.7
8
Systolic blood pressure, mm Hg

7
Change from baseline

6
5 *
4 3.6
3 2.4 *
2 ++
+
+
1
0
celecoxib 200 mg BID (n=21) naproxen 500 mg BID (n=21) etoricoxib 90 mg OD (n=21)

Compared to naproxen and etoricoxib, celecoxib only shows significant change compared to placebo. Meanwhile etoricoxib shows significant increase compared
to placebo, baseline, and celecoxib and naproxen.
+ Significantly different from placebo (P ≤ .05)
* Significantly different from baseline (P ≤ .05), placebo (P ≤ .05), and naproxen and celecoxib (P < .03)

• Systolic BP: Ambulatory systolic blood pressures were significantly higher than placebo for all treatments, with
moderately greater increases for etoricoxib relative to other active treatments on day 14.
• Diastolic BP : Ambulatory diastolic blood pressures were significantly higher than placebo for etoricoxib and naproxen
but not for celecoxib
26 Schwartz JI et al. Journal of Clinical Pharmacology, 2007;47:1521-1531
CONCERN Study (2017) – GI Safety in patients with cardio-
thrombotic diseases and arthritis after upper GI bleeding

• In patients at high risk of both cardiovascular and gastrointestinal

events who require concomitant aspirin and NSAID, celecoxib plus
proton-pump inhibitor is the preferred treatment to reduce the risk of
recurrent upper gastrointestinal bleeding
• Naproxen should be avoided despite its perceived cardiovascular safety

Chan FKL, Ching JYL, Tse YK, Lam K, Wong GLH, Ng SC, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding 16
(CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet. 2017;389(10087):2375–82.
 CV SAFETY
Celecoxib demonstrated similar incidence of CV events compared
to Naproxen and Ibuprofen
* P value for non-inferiority
Intention-To-Treat (ITT) On-Treatment (mITT)
Celecoxib vs. naproxen, HR 0.93 (0.76-1.12), P<0.001* Celecoxib vs. naproxen HR 0.90 (0.71-1.15), P<0.001*
100 Celecoxib vs. ibuprofen, HR 0.85 (0.70-1.04), P<0.001* Celecoxib vs. ibuprofen, HR 0.81 (0.65-1.02), P<0.001*
100
Ibuprofen vs. naproxen, HR 1.08 (0.90-1.31), P<0.02* Ibuprofen vs. naproxen HR 1.12 (0.89-1.4), P=0.025*
4
Patients with an Event (%)

80 4 80

Patients with an Event (%)

3
3
60 60
2
2

40 Celecoxib 40 Celecoxib
1 1 Naproxen
Naproxen
Ibuprofen Ibuprofen
0 20 0
20
0 6 12 18 24 30 0 6 12 18 24 30 36 42

0.0 0.0
0 6 12 18 24 30 0 6 12 18 24 30 36 42
Months since Randomization Months since Randomization

. Non-inferiority was demonstrated in all pairwise comparisons in both the ITT and MITT populations.

Nissen S et al. N Engl J Med. 2016 Dec 29;375(26):2519-29. 17

 Acute shoulder tendinitis/bursitis: Celecoxib 400
mg/day and naproxen significantly reduced pain
Primary Mean reduction in maximum pain
endpoint intensity at rest (VAS) at day 7

Improvement
Mean change (mm)

*
*p<0.05 celecoxib vs placebo;
† p<0.05 naproxen vs placebo *

Petri M et al. J Rheumatol. 2004;31:1614-1620

 In Post operative patient pain :
Celecoxib 400 mg and Ibuprofen 400 mg is comparable

Onset of analgesia of Celecoxib start from 22 min (median 28 min) & time to
use of rescue medication with celecoxib (>24 hours) was significantly longer
than with ibuprofen (10 hours, 58 minutes)
19
Cheung r et al 2007;29:2498-2510.
 Take home messages
• Goals in pain management are optimize pain relief and improved function with
minimized adverse effects.11
• Patients with mixed pain may benefit from combination therapy.
• Efficacy of Celecoxib :
– In acute pain :
• In acute ankle sprain : Reduce pain similar with Ibuprofen1
• In total knee arthroplasty : Effective in reduce post operative pain2, more rapid recovery2,3, and did not affect
perioperative blood loss2.
• In acute shoulder tendinitis/bursitis: Reduce pain similar with Naproxen4
• In post laparoscopic surgery : Significantly reduce post surgical pain5.
– In chronic pain :
• In Arthritis pain : Similar with Naproxen and Ibuprofen7
• In knee OA : Reduced pain in patients with no respond or no tolerate with Naproxen and Ibuprofen 8
• In knee or hip OA : Fewer OA flares in continuous use compare with intermittent use9
• In RA : Similar with Diclofenac for treatment of pain and inflammation with 3 times lower GI related AEs than
Diclofenac.10

1. Ekman EF et al. Am J Orthop (Belle Mead NJ). 2002;31:445-451; 2. Huang YM et al. BMC Musculoskelet Disord. 2008;9:77.; 3.Schroer et al. The Journal of Arthroplasty 2011; 6:2-7.; 4. Petri M et al. J Rheumatol.
2004;31:1614-1620.; 5. White PF et al. Can J Anesth 2007;54:342-348.; 6.Goldstein JL et al., Ali Pharmacol Ther 2007;25:1211-1222; 7. Nissen et al. NEJM. 2016;375 (26):25419 – 2529.; 8. Asmus MJ, Essex MN, Brown
BP, et al, Efficacy and tolerability of celecoxib in osteoarthritis patients who previously failed naproxen and ibuprofen: results from two trials Int. J. Clin. Rheumatol. (2014) 9(6), 551–558.; Strand V, SIMON LS,
DOUGADOS M, et al. Treatment of Osteoarthritis with Continuous Versus Intermittent Celecoxib. J Rheumatol 2011;38:2625-2634.; 10. Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, et al. Celecoxib
versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet. 1999;354(9196):2106–11. ; 11. Wong R et al. Prevalence of Arthritis and Rheumatic Diseases
Around the World: A Growing Burden and Implications for Health Care Needs. Arthritis Community Research and Evaluation Unit; Toronto, ON: 2010; 11. Farrar JT et al. Pain 2001; 94(2):149-58; Gilron I et al. CMAJ
2006; 175(3):265-75.;
 Take home messages (cont.)
• Safety profile of Celecoxib :
– GI safety :
• Fewer serious GI events than Naproxen or Ibuprofen.1
• 4x lower risk of GI AEs and lower incidence of Anemia than Diclofenac + Omeprazole. 2
• 2x lower risk of GI AEs and fewer Anemia than ns-NSAIDs.3
– CV & Renal safety:
• Similar CV events with Naproxen and Ibuprofen. 1
• Similar with Naproxen on major vascular events (while Etoricoxib has more events).4
• Lower renal events than Ibuprofen and similar to Naproxen.1
• Lower rate of hospitalization for hypertension than Ibuprofen. 1
• Similar with Naproxen and Etoricoxib in effect on ambulatory systolic BP than placebo with
greater increases on Etoricoxib. 5
• Similar with placebo on ambulatory diastolic BP (while Etoricoxib and Naproxen increase it
significantly). 5
– Celecoxib + PPI is the preferred treatment to reduce the risk of recurrent upper GI bleeding in patient
at high risk of both CV & GI events who require concomitant Aspirin and NSAID.6
– Less deaths from any cause than Naproxen and Ibuprofen. 1
• Addressing the benefits as well as GI and CV risk in OA patients who need NSAID, Celecoxib have role in
patient with high/low GI risk with/without CV risk.7
1. Nissen et al. NEJM. 2016;375 (26):25419 – 2529.; 2. Chan et al. Lancet. Early Online Publication, 17 June 2010.; 3. Cryer B, et al. Am J Gastroenterol 2013;108(3):392-400.; 4. Lancet 2013;382:769-779
(appendix tables).; 5. Schwartz JI et al. Journal of Clinical Pharmacology, 2007;47:1521-1531.; 6. Chan FKL, Ching JYL, Tse YK, Lam K, Wong GLH, Ng SC, et al. Gastrointestinal safety of celecoxib versus naproxen
in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet.
2017;389(10087):2375–82.; 7. Scarpignato 2015; BMC Medicine 2015:13-55
PREGABALIN

22
 Pharmacological Management of
Neuropathic Pain
Initiate treatment with one or more first-line treatments:
STEP 1

• α2δ ligands (gabapentin, pregabalin) • TCAs* (nortriptyline, desipramine)

• SNRIs (duloxetine, venlafaxine) • Topical lidocaine
(for localized peripheral pain)

• If there is partial pain relief, add another first-line medication

STEP 2

• If there is no or inadequate pain relief, switch to another

first-line medication

If first-line medications alone and in combination fail, consider

STEP 3

second-line medications (opioids, tramadol) or third-line medications

(bupropion, citalopram, paroxetine, carbamazepine, lamotrigine,
oxcarbazepine, topiramate, valproic acid, topical capsaicin,
dextromethorphan, memantine, mexiletine) or referral to pain specialist

*Use tertiary amine TCAs such as amitiptyline only if secondary amine TCAs are unavailable
Note: there is insufficient support for the use of nsNSAIDs in neuropathic pain
nsNSAID = non-specific non-steroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant
Dworkin RH et al. Mayo Clin Proc 2010 ; 85(3 Suppl):S3-14; Freynhagen R, Bennett MI. BMJ 2009; 339:b3002.
Pregabalin for acute and chronic pain in adults – Cochrane
Review
Background
• Antiepileptic drugs have been used in pain management since the 1960s.
Pregabalin is a recently developed antiepileptic drug also used in management of
chronic neuropathic pain conditions.

Objectives
• To assess analgesic efficacy and associated adverse events of pregabalin in acute
and chronic pain.

Main results
• There was no clear evidence of beneficial effects of pregabalin in established
acute postoperative pain. No studies evaluated pregabalin in chronic nociceptive
pain, like arthritis
• Pregabalin at doses of 300 mg, 450 mg, and 600 mg daily was effective in
patients with post-herpetic neuralgia, painful diabetic neuropathy, central
neuropathic pain, and fibromyalgia (19 studies, 7003 participants)
• Pregabalin at 150 mg daily was generally ineffective. Efficacy was demonstrated
for dichotomous outcomes equating to moderate or substantial pain relief,
alongside lower rates for lack of efficacy discontinuations with increasing dose
Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;1–60. 26
Pregabalin, celecoxib, and their combination for treatment
of chronic low-back pain

Objective: Results:
To compare the safety and efficacy of the
association of celecoxib and pregabalin with
monotherapy of each for treatment of
Drug Pain reduction
chronic LBP Celecoxib 12.4%
Pregabalin 10.4%
Methods:
Double-blinded, prospective randomized Celecoxib + Pregabalin 38.2%
trial
N=36 patients
Celecoxib (approximately 3–6 mg/kg/die) +
placebo; Pregabalin + Celecoxib
Pregabalin (approximately 1 mg/kg/die the (in patients with LANSS
first week and then 2–4 mg/kg/die) + score >12 = 51.8%
placebo;
[Largest pain
Celecoxib (approximately 3–6 mg/kg/die)
plus pregabalin (approximately 1 mg/kg/die
reduction group]
the first week and then 2–4 mg/kg/die)

Conclusion: Combination of celecoxib and pregabalin is more effective than monotherapy for
chronic LBP, with similar adverse effects

Romanò, C.L., Romanò, D., Bonora, C. and Mineo, G., 2009. Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain. Journal of Orthopaedics and Traumatology, 10(4), pp.185-191. 27
 Take home messages (cont.)
• Pregabalin has been found to have distinct pharmacokinetic advantages over
gabapentin
• Pregabalin efficacy:
– in post-traumatic peripheral neuropathic pain : More global improvement at
end-point with pregabalin than with placebo (68% vs. 43%; overall P < 0.01)1
– Pregabalin at doses of 300 mg, 450 mg, and 600 mg daily has proven efficacy in
patients with post-herpetic neuralgia, painful diabetic neuropathy, central
neuropathic pain, and fibromyalgia (19 studies, 7003 participants)2.
– Pregabalin provide significant pain relief for patients who were gabapentin
responders (P<0.025) with fewer AEs and improvement in quality of life 3
• In mixed pain chronic LBP :
– Combination of Celecoxib and Pregabalin is more effective than monotherapy
for chronic LBP, with similar adverse effects4

1. Seventer R Van, Bach FW, Toth CC, Serpell M, Temple J, Murphy TK, et al. Pregabalin in the treatment of post-traumatic peripheral neuropathic pain: a randomized double-blind
trial. Eur J Neurol. 2019;17(8):1–14.
2. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;1–60.
3. Toth C. Pain Med. 2010;11(3):456-65.
4. Romanò, C.L., Romanò, D., Bonora, C. and Mineo, G., 2009. Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain. Journal of Orthopaedics and
Traumatology, 10(4), pp.185-191.
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