Nonopioid medication in acute pain management

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Non-opioid medication in acute pain management

• Ian Power
• Anaesthesia, Critical Care and Pain Medicine
• www.anaes.med.ed.ac.uk/

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Prospect

• Procedure specific postoperative pain management
• Integrated surgical and anaesthetic approach
• www.postoppain.org

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Acute Pain Management Scientific Evidence (2nd
Edition)

• Physiology and Psychology of Acute Pain
• Assessment and Measurement
• Provision of safe and effective management
• Systemically administered analgesic drugs

• Regionally and locally administered analgesic
  drugs
• Routes of systemic drug administration
• Techniques of drug administration
• Non-pharmacological techniques

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Levels of evidence

• I Evidence obtained from a systematic review of
  all relevant randomised controlled trials.
• II Evidence obtained from at least one properly
  designed randomised controlled trial
• III-1 Evidence obtained from well-designed
  pseudo-randomised controlled trials (alternate
  allocation or some other method)
• NHMRC 1999

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4.2.1 Paracetamol

• Paracetamol is an effective analgesic for acute
  pain (Level I).
• Paracetamol is an effective adjunct to opioids
  (Level I).
• NSAIDs given in addition to paracetamol improve
  analgesia (Level I).
• IV paracetamol is an effective analgesic after
  surgery (Level II), is as effective as ketorolac
  (Level II) and equivalent to morphine after
  dental surgery with better tolerance (Level II).

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4.2.2 NSAIDs

• NSAIDs are effective analgesics for the acute
  pain of surgery, low back pain and renal colic
  (Level I).
• NSAIDs are effective adjunct to opioids (Level
  I).
• NSAIDs given in addition to paracetamol improve
  analgesia (Level I).

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4.2.3 Cox-2 inhibitors

• COX-2 inhibitors and NSAIDS are effective
  analgesics of similar efficacy for acute pain
  (Level I).
• COX-2 inhibitors are effective adjunct to opioids
  (Level II).

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4.2 Paracetamol, NSAIDs and COX-2 inhibitors

• Paracetamol is an effective analgesic for acute
  pain (Level I).
• NSAIDs and COX-2 inhibitors are effective
  analgesics of similar efficacy for acute pain
  (Level I).
• NSAIDs given in addition to paracetamol improve
  analgesia (Level I).
• With careful patient selection and monitoring,
  the incidence of NSAID-induced perioperative
  renal impairment is low (Level I).
• Paracetamol, NSAIDs and COX-2 inhibitors are
  valuable components of multimodal analgesia
  (Level II).

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Number-needed-to-treat (v placebo)

• NNT (95CI)
• Codeine 60 mg 16.7 (11-48)
• Paracetamol 1000 mg 3.8 (3.4-4.4)
• Morphine 10 mg (IM) 2.9 (2.6-3.6)
• Ketorolac 10 mg 2.6 (2.3-3.1)
• Ibuprofen 400 mg 2.4 (2.3-2.6)
• Diclofenac 50 mg 2.3 (2.0-2.7)
• Paracetamol 1G/ Codeine 60 mg 2.2 (1.7-2.9)
• Parecoxib 40 mg (iv) 2.2 (1.8-2.7)
• Lumiracoxib 400mg 2.1 (1.7-2.5)
• Diclofenac 100mg 1.9 (1.6-2.2)
• Oxford acute pain league table www.jr2.ox.ac.uk/ba
  ndolier/booth/painpag/Acutrev/Analgesics/Leagtab.h
  tml

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6. NSAIDs and COX-2 inhibitors

• NSAIDs (including COX-2 inhibitors) given
  parenterally or rectally are not more effective
  and do not result in fewer side-effects than the
  same drug given orally (Level 1).

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Safety of selective and non-selective NSAIDs

• New information on non-selective NSAIDs
• General advice on prescribing NSAIDs and coxibs
• Background
• Conclusions to date
• Prof G Duff
• Commission on Human Medicines
• Oct 2006
• www.mhra.gov.uk

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1. New information on non-selective NSAIDs

• Small increased risk of thrombotic attacks.
• Diclofenac (150 mg ) etoricoxib.
• Ibuprofen 1200mg or below - no increase of
  myocardial infarction.
• Naproxen - lower incidence of thrombotic risk
  than coxibs.
• All NSAIDs - risk greater with high doses, long
  term Rx.

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2. General advice on prescribing NSAIDs and coxibs

• Lowest effective dose, shortest time.
• Rx based on drug safety profiles and patient risk
  profiles.
• Dont switch without considering safety profiles.
• Concomitant aspirin (possibly other antiplatelet
  drugs) - greatly increase GI risks of NSAIDs and
  severely reduce any advantages of coxibs.

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3. Background

• 2000 - increased risk with coxibs?
• 2004 - voluntary withdrawal of rofecoxib.
• 2005 - European-wide review, coxibs
  contraindicated in IHD, cardiovascular disease,
  peripheral arterial disease.
• Non-selective NSAIDs?
• www.mhra.gov.uk

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4.Conclusions to date

• Coxibs - three additional events per 1000
  patients per year, compared with placebo.
• Some NSAIDs may be associated with a small
  increase in thrombotic events when used at high
  doses and for long term treatment.
• NSAIDs Product Information to be updated.
• CHA setting up a cross-specialty expert group to
  consider the safe use of these products.
• www.mhra.gov.uk

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European Medicines Agency

• The European Medicines Agency has concluded
  that the benefit-risk balance for non-selective
  NSAIDs remains favourable.
• Press Release
• Oct 2006

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Prospect

• Procedure specific postoperative pain management
• Integrated surgical and anaesthetic approach
• Cholecystectomy, total hip arthroplasty,
  hysterectomy.
• www.postoppain.org

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Prospect

• As with any surgical procedure, the techniques
  employed during the operation, as well as
  analgesic medication delivered pre-, intra- and
  post-operatively can have an impact on patient
  outcomes
• www.postoppain.org

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Prospect - laparoscopic cholecystectomy

• Pre-operative
• Institute analgesia in good time clonidine (if
  further data confirms benefit) dexamethasone
• Operative techniques
• Low pressure CO2 pneumoperitoneum (? Lavage,
  suction)
• Intra-operative analgesia
• Short-acting strong opioids intraperitoneal
  local anaesthetic at the end of surgery plus
  incisional local anaesthetic (nb dose) clonidine
  (if further data confirms benefit).

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Prospect - laparoscopic cholecystectomy

• Post-operative analgesia
• NSAID
• COX-2 inhibitors
• Paracetamol
• Weak opioids
• Epidural local anaesthetics/ opioids (high-risk,
  open)
• Consider ketamine

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Prospect - laparoscopic cholecystectomy

• Up to six hours post-operatively (including the
  PACU)
• A step-up approach should be employed. However,
  for patients with more severe pain, starting at
  step 2 or 3 may be appropriate
• Step 1 NSAID/Cox-2 paracetamol
• Step 2 Add weak opioids if pain persists
• Step 3 Add strong short -acting opioids if pain
  persists
• (After six hours use low doses of strong opioids
  in Step 3)

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9. Specific clinical situations

• 9.1 Postoperative pain
• 9.2 Acute spinal cord injury pain
• 9.3 Acute burns injury pain
• 9.4 Acute back pain
• 9.5 Acute musculoskeletal pain
• 9.6 Acute medical pain
• 9.7 Acute cancer pain
• 9.8 Acute pain management in intensive care
• 9.9 Acute pain management in emergency departments

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9.1.3 Day surgery

• 5.3 incidence of severe pain in the first 24
  hours.
• BMI, duration of anaesthesia, type of surgery.
• The best predicator of severe pain at home is
  inadequate analgesia in the first few hours after
  surgery.

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9.7 Acute cancer pain

• Acute pain in patients with cancer often signals
  disease progression sudden severe pain should be
  recognized as a medical emergency.

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10. Specific patient groups

• 10.1 The paediatric patient
• 10.2 The pregnant patient
• 10.3 The elderly patient
• 10.4 Aboriginal and Torres Strait Islander
  patients
• 10.5 Other ethnic groups and non-English speakers
• 10.6 The patient with obstructive sleep apnoea
• 10.7 The patient with concurrent hepatic or renal
  disease
• 10.8 The opioid-tolerant patient
• 10.9 The patient with a substance abuse disorder

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Nitroxyparacetamol

• Nitroparacetamol exhibits anti-inflammatory and
  anti- nociceptive activity. al- Swayeh OA et al.
  Br J Pharmacol 20001301453-1456
• A comparison of the effect of nitroparacetamol
  and paracetamol on liver injury. Futter LE et al.
  Br J Pharmacol 200113210-12

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Nitroxyparacetamol

• Acetaminophen hepatotoxicity NO to the rescue.
  Wallace JL. Br J Pharmacol 20041431-2
• There is also substantial evidence that a
  NO-releasing derivative of acetaminophen offers
  several advantages over acetaminophen itself,
  including enhanced analgesic potency and reduced
  liver toxicity.

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Nitroxyparacetamol

• Low doses of nitroparacetamol or dexketoprofen
  trometamol enhance fentanyl antinociceptive
  activity. Gaitan G et al. Eur J Pharmacol
  2003481181-188.
• Enhancement of fentanyl antinociception by
  subeffective doses of nitroparacetamol (NCX-701)
  in acute nociception and in carrageenan-induced
  monoarthritis. Gaitan G et al. Life Sciences
  20057785-95.

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4.3.2 Adjuvant drugs - NMDA antagonists

• Ketamine has an opioid-sparing effect in
  postoperative pain although there is no
  concurrent reduction in opioid-related side
  effects (Level I).
• NMDA receptor antagonist drugs may show
  preventive analgesic effects (Level I).
• Ketamine improves analgesia in patients with
  severe pain that is poorly responsive to opioids
  (Level II).
• Ketamine may reduce opioid requirements in
  opioid-tolerant patients (Level IV).

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4.3.4 Adjuvant drugs - Anticonvulsant drugs

• Anticonvulsants are effective in the treatment of
  chronic neuropathic pain states (Level I).
• Perioperative gabapentin reduces postoperative
  pain on movement and opioid requirements (Level
  I).

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4.3.5 Adjuvant drugs - Membrane stabilisers

• Membrane stabilisers are effective in the
  treatment of chronic neuropathic pain states,
  particularly after peripheral nerve trauma (Level
  I).
• Perioperative intravenous lidocaine reduces pain
  on movement and morphine requirements following
  major abdominal surgery (Level II).

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Gabapentin, pregabalin

• The analgesic effects of perioperative gabapentin
  on postoperative pain A meta-analysis. Hurley RW
  et al. Regional Anesthesia and Pain Medicine
  2006 3237-247.
• The analgesic efficacy of celecoxib, pregabalin,
  and their combination for spinal fusion surgery.
  Reuben SS et al. Anesth Analg 20061031271-1277.

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Acute neuropathic pain

• pain initiated or caused by a primary lesion or
  dysfunction in the nervous system (Merskey
  Bogduk 1994)
• burning, shooting, stabbing
• paroxysmal, spontaneous
• dysaesthesia, hyperalgesia, allodynia,
  hypoaesthesia
• regional autonomic features
• phantom phenomena

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Postoperative neuropathic pain

• 1-4?
• Nerve injury?
• Persistent, severe
• Diagnose early and treat

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Neuropathic pain

• 31. Anticonvulsants and antidepressants have been
  shown by meta-analysis to be effective in the
  treatment of neuropathic pain (I - McQuay 1996)

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Treatment of neuropathic pain

• Drug class Example Level
• Tricyclics Amitryptiline, doxepin I
• Anticonvulsants Carbamazepine, valproate I
• Newer anticonvulsants Gabapentin, lamotrigine I
• Membrane stabilisers Lidocaine II
• Corticosteroids Dexamethasone II
• Alpha2 agonists Clonidine II
• NMDA antagonists Ketamine, dextromethorphan II

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Anticonvulsants for neuropathic pain NNT -
carbamazepine

• Efficacy Adverse Severe
• events effects
• Trigeminal neuralgia 2.6 3.4 24
• Diabetic neuropathy 3.0 2.5 20
• McQuay and Moore 1998

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Non standard acute pain problems

• Acute spinal cord injury
• Acute postamputation pain syndromes
• Acute medical painAbdominalAcute herpes
  zosterNeurological disorders (Multiple
  sclerosis, Stroke, Guillain-Barre)

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Acute spinal cord injury

• Pain
• Nociceptive (somatic, visceral)
• Neuropathic (central pain)
• Phantom
• CRPS

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Taxonomy (Siddall 2002)

• Type Location Description
• Neuropathic Above level Area of sensory
  preservation
• At level Segmental pain
• Below level Pain below the injury
• Other CRPS
• Nociceptive Somatic Musculoskeletal procedure
  related dysreflexic headache
• Visceral Urinary tract (e.g. calculi)

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Treatment of acute neuropathic pain after spinal
cord injury

• Opioids
• Ketamine
• Lidocaine
• Antidepressants
• Anticonvulsants

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• IV opioids, ketamine and lignocaine (lidocaine)
  decrease acute spinal cord injury pain (Level II)
  
• Gabapentin is effective in the treatment of acute
  spinal cord injury pain (Level II)
• (No specific evidence for the treatment of acute
  nociceptive and visceral pain in spinal cord
  injury patients. Treatment is based on evidence
  from other studies of nociceptive and visceral
  pain)

Acute Pain Scientific Evidence Edition 2 ANZCA
2005
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Acute spinal cord injury pain

• 22 year old male
• RTA - spinal injury T12, neurological deficit
• Surgical fixation
• PCA fentanyl, paracetamol for analgesia
• 12 to 24 hours - severe neuropathic pain, rapidly
  increasing PCA fentanyl use

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Acute spinal cord injury pain

• Lidocaine 0.5 to 1 mg/kg/hour(nb PCA fentanyl)
• Then,
• Gabapentin
• Paracetamol, oral opioid (oxycodone), ibuprofen

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Acute postamputation pain syndromes

• Stump pain, localised to the site of the
  amputation. Acute - usually nociceptiveChronic
  - usually neuropathic
• Phantom sensation
• Phantom pain (preamputation pain, stump pain,
  chemotherapy)

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Acute postamputation pain syndromes

• There is a lack of evidence to guide specific
  treatment of postamputation pain syndromes (Level
  I).
• Continuous regional blockade via nerve sheath
  catheters provides effective postoperative
  analgesia after amputation, but has no
  preventive effect on phantom limb pain (Level
  II).
• Calcitonin, morphine, ketamine, gabapentin and
  sensory discrimination training reduce phantom
  limb pain (Level II).

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Acute postamputation pain syndromes

• Ketamine and lignocaine (lidocaine) reduce stump
  pain (Level II).
• Perioperative epidural analgesia reduces the
  incidence of severe phantom limb pain (Level
  III-2).

Acute Pain Scientific Evidence Edition 2 ANZCA
2005
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Acute postamputation pain syndrome

• 46 year old female
• Presented acutely with a gangrenous arm
• Severe pain
• Septic, confused, tachycardic, hypotensive,
  acidotic, hypoxic
• History of alcohol abuse
• Abnormal liver function tests

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Acute postamputation pain syndrome

• Surgery - general anaesthesia, interscalene nerve
  block, ketamine, opioidDay 1-3
• Postoperative pain relief ketamine 10 mg/ hour
  sc, opioid (oxycodone), paracetamol, gabapentin
• Stump pain - controlled
• Phantom sensation - immediate
• Phantom pain - immediate, controlled

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Acute postamputation pain syndrome

• Stump pain - worsened day 3-5 (Rx oxycodone
  increased TENS added)
• Phantom sensation - continuous
• Phantom pain increased from day 3, tricyclic
  added to gabapentin (opioid, TENS)

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