Drugs for Pain Relief

by Nik Ahmad Shaiffudin Nik Him, Azizul Fadzi

Introduction

A patient presented with pain at the Emergency Department (ED) commonly un-recognized, under-treated and delayed in getting treatment. Prompt recognition and alleviation of pain should be a priority when treating patient suffered from pain. There are many drugs available for pain relief. Optimal control of pain is essential for good patient care. It prevents an adverse physiological and psychological effects, reduce the incidence of chronic pain, postoperative morbidity and facilitate earlier discharge from the hospital.

Drugs for pain relief may be used for:

  1. Acute pain
  2. Chronic pain

Acute versus Chronic Pain

Pain is an unpleasant feeling. Sensory neurons convey it to the brain by as a result of injury, disease, or emotional disorder. Acute pain is defined as pain less than 6 months duration with a known cause and disappears when the problem resolves. Chronic pain occurs when pain lasts more than 6 months duration, persists beyond the healing time and usually the cause may not be determined (International Association for the study of pain, 2007).

The scientific approach to pain management demands a step-wise approach, which utilizes lower risk interventions first (WHO, 1996) especially in acute pain management. It is important to understand the different pain mechanisms of chronic pain as well as evidence-based multi-mechanistic treatment. It is also essential to provide individualized treatment. Pharmacological and non-pharmacological aspect is as equally important in chronic pain management at decreasing pain and increasing functioning of chronic pain patients during activity of daily livings.

The classes of medications used in the treatment of pain (Adapted from ACPA resource guide to chronic pain medication & treatment, 2015) include:

  1. Non-opioids (simple, non-selective and selective COX-2 inhibitors) e.g. aspirin, NSAIDs, and acetaminophen and celecoxib.
  2. Opioids (weak and strong) e.g., tramadol, morphine, codeine, hydrocodone, and oxycodone.
  3. Adjuvant analgesics e.g. antidepressants, anticonvulsants
  4. Local analgesia, e.g. lidocaine patch
  5. Others: Medications with no direct pain-relieving properties may also be prescribed as part of a pain management plan e.g. laxative, anti-emetic, steroids, bisphosphonates, muscle relaxant and anti-spasmodic

The tables below shows some specific information about these agents.

Non-opiods (Simple analgesic)

Drug Recommended DosagesSide Effects Cautions and ContraindicationsComments
Paracetamol0.5 - 1gm, 6 - 8 hourly
Max: 4g/day
Reduce maximum dose 50%-70% in patients with hepatic impairment
RareHepatic impairmentPreferred drug in elderly.

Liver damage following over dosage.

Maximum dose 4 g daily.
Perfalgan (IV)
Aqueous solution: 10mg/ml paracetamol, available in 50ml and 100ml vials
>50 kg, 1 g 6 hourly up to max 4g/day
10-50 kg, 15 mg/kg/dose
max 60mg/kg in 4 divided doses

Administration:
Infusion over 15 minutes.
Renal & hepatic impairement: minimum interval between doses should not be less than 6 hours
Hepatic impairmentImportant to consider the total dosage of paracetamol used i.e. to include dosage of suppositories and oral preparations.
Provided by author

Non-Opioid (Non-Selective NSAIDs)

Drug Recommended DosagesSide Effects Cautions and ContraindicationsComments
Aspirin 325 to 650 mg orally or rectally every 4 hours as needed, not to exceed 4 g/day.Peptic ulcer,
GI bleed,
Platelet dysfunction,
Renal failure,
Hypertension
Allergic reaction in susceptible individuals,
Increase in CVS events

Same for below agents
Gastroduodenal ulcer
Asthma
Bleeding disorder
Renal dysfunction
Ischaemic heart disease
Cerebrovascular disease
Inflammatory bowel disease

Same for below agents
Current data suggest that increased CVS risk may be an effect of the NSAIDs/Coxib class.

Physicians and patients should weigh the benefits and risks of NSAIDs/Coxib therapy.

Concurrent use with aspirin inhibits aspirin‟s antiplatelet effect (mechanism unclear)

Same for below agents
Diclofenac Sodium50 - 150 mg daily,
8 - 12 hourly
Max: 200 mg/day
Mefenemic Acid250-500 mg 8 hourly
Ibuprofen

200-400 mg, 8 hourly
Max: 2400 mg/day
Elderly patients: 200 mg 3 x a day
Naproxen500-550mg BD
Elderly patients; 220 mg BD
Ketoprofen Patch: 30 -60 mg BD
Topical; PRN
Ketorolac IV: 10-20 mg BD
( max 3days)
Meloxicam 7.5-15 mg daily
Max: 15 mg /day
Provided by author

Non-Opioids ( Selective Cox-2 Inhibitors)

Drug Recommended dosagesSide Effects Cautions and ContraindicationsComments
Celecoxib 400mg BD in acute pain (48 hours only)
200-400 mg daily (for longer term use)
<18 years : not recommended
Elderly patients: 100 mg daily
Renal impairment
Allergy reaction in susceptible individuals
Increase in CVS events
Hypertension

Same for below agents
Ischaemic heart disease
Cerebrovascular disease
Hypersensitivity to sulfonamides.
Higher doses associated with higher incidence of GIT, CVS side effects.
Patients with indications for cardioprotection require aspirin supplement
Uncontrolled Hypertension

Same for below agents
Associated with lower risk of serious upper gastrointestinal side effects compared to traditional NSAIDs

Use the lowest effective dose for the shortest duration necessary
Etoricoxib 120 mg daily in acute pain (48 hours only)
60 - 90 mg daily (for longer term use)
Elderly patients 30 mg daily
Parecoxib 20-40mg 6-12 hourly (max 80mg/day for max duration of 48 hours )
Elderly (>65 years & <50kg) reduce to half the dose with a maximum daily dose of 40mg.

Renal & hepatic impairment :
Do not use
Provided by author

Opioids (Weak opioids)

Drug Recommended dosagesSide Effects Cautions and ContraindicationsComments
Tramadol 50 - 100 mg, 6 - 8 hourly
Max: 400 mg/day
Dizziness
Nausea
Vomitting
Constipation
Drowsiness
Risk of seizures in patients with history of seizures and with high doses
In elderly, start at lowest dose (50 mg) and maximum 300 mg daily
Interaction with TCA, SSRI and SNRI
Dihydrocodeine tartrate
(DF118)
30 - 60 mg,
6 - 8 hourly
Max: 240 mg/day

Renal dysfunction &:dialysis patient: do not use

Hepatic dysfunction:
do not use
Nausea
Vomiting Constipation Drowsiness
Respiratory depression
Acute alcoholism
Paralytic ileus
Raised intracranial pressure
Metabolites can accumulate causing adverse effects

In severe hepatic impairment, codeine may not be converted to the active metabolite- morphine.
Provided by author

Combinations of opioids and paracetamol

Drug Recommended dosagesSide Effects Cautions and ContraindicationsComments
Paracetamol 500 mg + Codeine 8 mg 1 - 2 tablets, 6 - 8 hourly
Max: 8 tablets/day
Constipation Hepatic impairmentDecrease in side effect profile of Codein/ tramadol respectively and paracetamol while maintaining efficacy
Paracetamol 325 mg + Tramadol 37.5 mg1 - 2 tablets, 6 - 8 hourly
Max: 8 tablets/day
Nausea
Vomiting
Drowsiness
Hepatic impairment, Epilepsy Same as above
Provided by author

Opioids ( Strong opioids)

Drug Recommended dosagesSide Effects Cautions and ContraindicationsComments
Morphine SC (Adults):
<65 yrs: 5mg-10 mg 4 hrly
>65 yrs: 2.5 mg-5mg 4hrly

IV: Follow morphine pain protocol (Appendix)

Oral: Starting dose 5- 10 mg,
4 hourly of IR

Elderly: 2.5 - 5 mg, 4 - 6 hourly of IR
Nausea
Vomiting
Pruritus
Sedation
Constipation
Respiratory depression
Myoclonus
Acute bronchial asthma

Respiratory depression

Head injuries,Renal and hepatic dysfunction: needs dose adjustment
Metabolites can accumulate causing increased therapeutic and adverse effects

Both parent drug and metabolites can be removed with dialysis, watch for “rebound” pain effect
Fentanyl To be prescribed by APS team only

Renal dysfunction : appears safe, however, a dose reduction is necessary


Dialysis patients : appears safe

Hepatic dysfunction : appears safe, generally no dose adjustment necessary

Nausea
Vomiting
Sedation
Constipation
Respiratory depression
No active metabolites and appears to have no added risk of adverse effects; monitor with high long term user

Metabolites are inactive, but use caution because fentanyl is poorly dialysable

Decrease hepatic blood flow affects metabolism more than hepatic failure.
Oxycodone IR
(oxynorm)
Starting dose (oral):
5 -10 mg 4 - 6 hourly

Renal dysfunction : Use cautiously with careful monitoring, adjust dose if necessary

Dialysis patients:
do not use

Hepatic dysfunction:
Use cautiously and monitor patient carefully for symptoms of opioid overdose
Decrease initial dose by 1/2 to 1/3 of the usual amount
Elderly patients : 2.5-5 mg every 4-6 h
Nausea
Vomiting
Sedation
Constipation
Respiratory depression
Acute bronchial asthma
Respiratory depression
Con-comittent used of sedative drugs
Head injuries,Renal and hepatic dysfunction: needs dose adjustment
Metabolites and parent drug can accumulate causing toxic and CNS-depressant effects

In severe hepatic impairment, the parent drug may not be readily converted to metabolites
Provided by author

Adjuvant Therapies

Drug Recommended dosagesSide Effects Cautions and ContraindicationsComments
Antidepressant
Amitriptyline Start with 10 - 25 mg nocte.
Increase weekly by 25 mg/day to a max of 150 mg/day

Elderly patients: 10 mg ON
Anticholinergic effects
e.g. dry mouth, drowsiness, urinary retention, arrhythmias
Not recommended in elderly patients with cardiac disease, glaucoma, renal disease

Nortriptyline may be a suitable alternative and better tolerated in elderly at similar doses

Interaction with Tramadol
Significant risk of adverse effects for the elderly

Duloxetine 30 - 60 mg/day
Max: 120 mg/day
Gastrointestinal disorder
Excessive sweating CNS disorder

Narrow-angle glaucoma
Potent CYP1A2 inhibitors
Concomitant use of MAOIs
Hypertension

Interaction with Tramadol
Anticonvulsants
Carbamazepine 100 - 1600 mg/day

Elderly patients: 100 mg daily
Dizziness
Ataxia
Fatigue
Leucopenia
Nausea
Vomiting
Drowsiness

Increased ocular pressure
Latent psychosis
Confusion
Agitation
Well tolerated.
Serious adverse events are rare
Gabapentin Day 1: start at 300mg
Day 2: 300 mg 12 hourly
Day 3: 300 mg 8 hourly
Thereafter, increase by 300 mg/day every 1- 7 days
Max: 3600 mg/day

Elderly patients : 100mg daily

Drowsiness
dizziness
GI symptoms
Mild peripheral oedema
Dose adjustment needed in renal impairment

However, need to monitor sedation, ataxia, oedema,
hepatic trans-aminases, blood count , serum creatinine, blood urea and electrolytes
Pregabalin Start with 150 mg/day (in 2 divided doses). If needed, increase to 300 mg/day after 3 - 7 days intervals,
then if needed, increase to 600 mg/day after 7 days interval Max: 600 mg/day
Elderly patients : 50 mg at bedtime
Same as aboveSame as aboveSame as above
Provided by author

Other agents used for analgesia or an adjunct to analgesics

Drug Recommended dosagesSide Effects Cautions and ContraindicationsComments
Bisphosphonates
Pamidronate 60 - 90 mg as a single infusion over 2 - 4 hrs every 4 weeks Asymptomatic hypocalcemia, hypophosphataemia, hypomagnaesemia
Flu-like symptoms
Mild fever
Local injection -site reactions
Malaise
Rigor
Hypersensitivity to biphosphonates.

Hyperparathyroidism

In renal impairment, reduce dose and increase infusion duration required

In patients with poor dental hygiene, there is higher risk of ONJ. Dental referral is advised
Rehydrate patients with normal saline before or during treatment.

Not to be given as bolus injection
Zoledronate Acid 4 mg as 15 min IV infusion every 3 - 4 weeks Hypertermia
Flu-like symptoms
Headache
Hypersensitivity
Osteonecrosis of jaw
Same as aboveSame as above
Steroids as anti inflammatory
Dexamethasone Oral/ IV/SC:
8 - 16 mg daily or divided doses (initial dose), then to reduce to lowest possible dose (usually 2 mg/day)

Elderly patients :5 mg daily and taper as soon as feasible

Increased or decreased appetite
Insomnia
Indigestion
Nervousness
Myopathy
Oral candidiasis
Adrenal suppression
Peptic ulcer disease Concomitant NSAIDs use
Liver or cardiac impairment
Should be given before 6 pm to reduce risk of insomnia

Efficacy may reduce over 2 - 4 weeks
Use lowest possible dose to prevent side effects.

Anticipate fluid retention and glycemic effects in short-term use and CV and bone demineralization with long-term use
Monitor for rash or skin irritation
Lignocaine (topical)
Lignocaine 5% Elderly patients : 1-3 patches for 12 hours per day Monitor muscle weakness, urinary function, cognitive effects, sedation
Muscle relaxant
Baclofen 5 mg -15 mg daily Avoid abrupt discontinuation because of CNS irritability
Laxatives
Lactulose 15 - 45 ml orally 6 - 8 hourly Bloating
Epigastric
pain
Flatulence
Nausea
Vomiting
Cramping

Hypersensitivity to lactulose products
Galactosemia

Patients requiring a galactose free diet
May be mixed with fruit juice, water or milk
Reasonable fluid intake is required for efficacy
Bisacodyl 5 - 10 mg orally, 1 - 2 times daily
Max: 30 mg/day

Atony of colon Intestinal obstruction
Antiemetic
Metoclopramide 10 - 20 mg
6 - 8 hourly
Extrapyramidal reactions
Dizziness
Drowsiness

Epileptic patients Gastrointestinal hemorrhage
Haloperidol 0.5-3 mg ON Extrapyramidal Syndromes
Dystonia
Prolonged QT interval
Neuroleptic Malignant
Syndrome
Concomitant use with other psychotropic drugs may increase Extra- pyramidal Syndromes
Granisetron 1 mg 12 hourly Constipation Progressive ileus and/or gastric distension may be masked Should not be used as first line.
Not for long term use.
Ondansetron 8 mg 12 hourly Headache
Sensation of flushing or warmth in the head and epigastrium
Constipation
Pregnancy and lactation
Hepatic impairment
Prochlorperazine 10 - 30 mg daily in divided doses
Severe nausea and vomiting: 20 mg stat followed by 10 mg after 2 hours
For prevention: 5 - 10 mg 8 - 12 hourly
Extrapyramidal symptoms
Dry mouth
May increased risk of seizure with Tramadol
Provided by author

Management of Major Opioid Complications

Hypoventilation* or Unarousable

  1. Stop infusion
  2. Oxygen12L/min.via Hudsonmask
  3. Naloxone(Narcan) 0.01mg/kg
    *Hypoventilation if
    • Respiratory rate < 10 / min. for > 5 years old
    • Respiratory rate < 15 / min. for 1 – 5 years old
    • Respiratory rate < 20 / min. for < 1 year old.

Apnoea

  1. Stop infusion
  2. Ventilate with bag and mask(100%oxygen)
  3. Check pulse, if absent start CPR
  4. Naloxone(Narcan) 0.01mg/kg

Severe Vomiting

  1. Before any antiemetic, always ensure that patient is adequately hydrated, good analgesia, and that hypoglycemia and hypotension are not causative factors.
  2. Reduce or stop infusion if necessary.
  3. Give Ondansetron 0.15mg/kg IV or Granisetron 0.05mg/kg IV over 10 min.

Hints and Pitfalls

The hints

  1. More than 75% of ED presenting complain is related to pain.
  2. Severe pain creates a barrier to obtain an adequate history and physical exam. It can be easily resolved by giving early pain medication thus facilitate better patient care.
  3. Assessment of pain severity is challenging that requires a holistic approach. Thus, regardless of one’s preferred approach, the assessment method should be used and supplemented with regular pain reassessments.
  4. Drugs for pain relief should be chosen appropriately and to keep it simple as polypharmacy is associated with more side effects.
  5. Pain medication should be given within 20–25 minutes of initial evaluation at ED including the plan of treatment. The benefits not only improving patient comfort but also had physiological advantages, e.g. reduction of pain-related tachycardia in acute coronary syndrome and aortic dissection.
  6. History of medication that had been taken and failed prior to ED presentation is crucial. It should be known that medications which have failed at home are likely to fail in the ED.
  7. Always consider targeted analgesia.
    • No doubt non-specific analgesics (e.g., NSAIDs, opioids) useful in the ED but the risk of side effects may be significant in certain population thus targeted analgesia is the best approach.
    • ED providers should consider a specific and effective therapy available, e.g. local nerve block
  8. In acute severe pain, fast administration of drugs for analgesia is better and preferable.
    • The key with regard to analgesia administration route is neither “always use IV” and nor “the more severe the pain, the more likely IV is the right route.”
    • In difficult IV access or IV route’s disadvantages seem to outweigh its benefits, alternative approaches may be best
  9. Any suspicions of drug abuse, e.g. preference or insist on certain opioids, ECP should obtain a detailed history and consider for referral to psychologist for evaluation for drug abuse
  10. Pain care is an ongoing process in the ED and after discharge.
    • Ignorance of the principle of ongoing pain treatment lead to risks of “wind-up” and increased analgesia requirements
    • Proper pain care saves time overall (as for a fracture), it will likely be necessary for at least a few days and often more after discharge

The pitfalls

  1. The response to drugs for pain relief varies for individual. Therefore, there is no uniform pain threshold.
    • Heredity, socio-cultural level, energy level, coping skills, and prior experiences with pain define pain tolerance among individuals.
  2. Neglect of pain medications at ED when busy in resuscitating the patient.
    • Assessment of pain is a necessary, but not a sufficient component in pain care. Pain score should be monitored with the aim of addressing relief (“correcting” where possible).
    • Pain is inevitable whereas suffering is optional, thus emergency care provider’s needs to treat the pain or acknowledge the reason for non-treatment as such should occur both in conversations with the patient (or family) and in the medical record.
  3. Failure to anticipate major complications of pain relief medication, e.g. toxicity, anaphylaxis reaction.
    • Close monitoring during intravenous administration of pain medication to identify major complication is preferred.
    • Early and systematic approach in management of major complication can improve the morbidity and mortality
  4. Unrelieved pain has adverse physical and psychological consequences.
    • ECP should encourage the reporting of pain by individuals who are reluctant to discuss pain, deny pain when it is likely to present, or fail to follow through on prescribed pain relief medications.

Special considerations

Pediatric

Pain management in the pediatric population is challenging and they are at higher risk for under-recognized and under-treated. Neonates and even premature babies can and do feel pain. Pain experienced by children is no less and may even be more than that experienced by an adult. Children react to and report pain in different ways e.g. becomes quiet or withdrawn instead of crying.

The lack of IV access (time-consuming and painful) and unwarranted fears on the use of pain medication in children especially opioids is a common problem. Therefore, alternative analgesia routes such as nasal medication administration are helpful in younger patients.

Geriatric

Being an elderly not only had a higher risk for inadequate pain assessment but also to suffer untoward side effects of the pain relief medication especially in the demented patient. ECP need to weight out the risks and benefits of analgesia and should be discussed with patients and family members. It may be releived through the use of opioid-sparing analgesic regimens or employment of specific therapies (e.g., regional nerve blocks for hip fractures).

Pregnant patient

Poor acute pain management may lead to chronic pain and is associated with hypertension, anxiety, and depression. Commonly prescribed pain medications are relatively safe in pregnancy. There is no evidence showing analgesics increases the risk of major malformations. However, NSAIDs should not be used after 32 weeks’ gestation because of the possibility of bleeding effects. If opioids are used with caution during the pregnancy, the infant should be observed carefully for any signs of withdrawal. This is called as neonatal abstinence syndrome.

Drugs seeking behavior patient

Healthcare providers should have a sound understanding of the anatomy, physiology, and psychology of addictive behaviors. A focused history and examination should concentrate on items that can indicate inconsistencies or falsifications associated with inappropriate drug-seeking behavior. It was always difficult as a decision has to be made between “losing” to drug seekers and denying analgesia to patients who are genuinely in need. It is best to give patients the benefit of the doubt with due diligence.

References and Further Reading

  1. Todd KH, Sloan EP, Chen C et al. Survey of pain etiology, management practices and patient satisfaction in two urban emergency departments. CJEM 2002; 4(4):252-8
  2. Hue Jung Park and Dong Eon Moon. Korean J Pain 2010 June; Vol. 23, No. 2: 99-108 , ISSN 2005-9159 DOI:10.3344/kjp.2010.23.2.99
  3. Hassett AL, Williams DA. Non-pharmacological treatment of chronic widespread musculoskeletal pain. Best Pract Res Clin Rheumatol. 2011 Apr;25(2):299-309. doi: 10.1016/j.berh.2011.01.005.
  4. Brown J, Klein C, Lewis B et al. Emergency Department analgesia for fracture pain management. Ann Emerg Med 2003;42(2):197-205
  5. Stahmer SA, Shofer FS, Marino A et al. Do Quantitative Changes in Pain Intensity Correlate with Pain Relief and Satisfaction? Acad Emerg Med 2008; 5(9): 851-7
  6. S. H.Thomas and S. Shewakramani, “Prehospital trauma analgesia,” Journal of Emergency Medicine, vol. 35, no. 1, pp. 47–57, 2008.
  7. D. E. Fosnocht, E. R. Swanson, and P. Bossart, “Patient expectations for Pain Medication delivery,” American Journal of Emergency Medicine, vol. 19, no. 5, pp. 399–402, 2001.
  8. S.Thomas, Ed., Emergency Department Analgesia: An Evidence- Based Guide, Cambridge University Press, Cambridge, UK, 1 edition, 2008.
  9. J. Lotsch, C. Walter, M. J. Parnham, B. G. Oertel, and G. Geisslinger, “Pharmacokinetics of non-intravenous formulations of fentanyl,” Clinical Pharmacokinetics, vol. 52, pp. 23–36, 2013.
  10. S. H. Thomas, “Fentanyl in the prehospital setting,” American Journal of Emergency Medicine, vol. 25, no. 7, pp. 842–843, 2007.
  11. L. Drendel, R. Lyon, J. Bergholte, and M. K. Kim, “Outpatient pediatric pain management practices for fractures,” Pediatric Emergency Care, vol. 22, no. 2, pp. 94–99, 2006.
  12. A.W. Lozner, A. Reisner,M. L. Shear et al., “Pain severity is the key to emergency department patients’ preferred frequency of pain assessment,” European Journal of Emergency Medicine, vol. 17, no. 1, pp. 30–32, 2010.
  13. Bruehl S, Chung OY, Jirjis JN, Biridepalli S. Prevalence of clinical hypertension in patients with chronic pain compared to non-pain general medical patients. Clin J Pain. 2005;21(2):147–53.
  14. Whitten CE, Donovan M, Cristobal K. Treating chronic pain: new knowledge, more choices. Permanente J. 2005;9(4):9–18.  Available from: http://xnet.kp.org/permanentejournal/fall05/pain3.html.  Accessed 2006 Jan 15.
  15. Malaika Babb, Gideon Koren, Adrienne Einarson. Treating pain during pregnancy. Can Fam Physician. 2010 Jan; 56(1): 25, 27. PMCID: PMC2809170
  16. Guidelines on the Safe Practice of Acute Pain Management December 2014. The Hong Kong College of Anaesthesiologists (HKCA)
  17. Thorson D, Biewen P, Bonte B, Epstein H, Haake B, Hansen C, Hooten M, Hora J, Johnson C, Keeling F, Kokayeff A, Krebs E, Myers C, Nelson B, Noonan MP, Reznikoff C, Thiel M, Trujillo A, Van Pelt S, Wainio J. Acute Pain Assessment and Opioid Prescribing Protocol. Institute for Clinical Systems Improvement. Published January 2014.  www.icsi.org

Useful Links

  1. International Association study of pain. http://www.iasp-pain.org/
  2. Management of Pain in Adults – Best Practice Guideline, December 2014. The College of Emergency Medicine. www.collemergencymed.ac.uk
  3. Pain Management Handbook, Medical Development Division, Ministry Of Health Malaysia, October 2013. ISBN 978-967-0399-38-6. www.moh.gov.my
  4. World Health Organization (1996). Cancer pain relief. With a guide to opioid availability (2 ed.). Geneva: WHO. ISBN 92-4-154482-1.
  5. ACPA Resource Guide to Chronic Pain Medication & Treatment 2015 Edition. American Chronic Pain Association. Web Site http://www.theacpa.org
  6. A Guide to Safe Use of Pain Medicine from the Food and Drug Administration (FDA).
    Web Site http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm095742.pdf
  7. Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM; APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine (2010), Acute Pain Management: Scientific Evidence (3rd edition), ANZCA & FPM, Melbourne. http://www.anzca.edu.au/ resources/books-and-publications/