Methadone and It’s Use in Anesthesia · The morphine group had a higher total pain score for the 48hr study period (p

Methadone & It’s Use in Anesthesia

Patricia G. Yocum, SRNAWyoming Valley Health Care System/University of Scranton School of Nurse Anesthesia

April 14, 2007

ObjectivesTo discuss the use and effectiveness of methadoneTo discuss the pharmacokinetics and pharmacodynamics of methadoneTo discuss how methadone compares with other narcoticsTo discuss dosing options of methadoneTo discuss potential complications of methadoneTo discuss the need the for additional and current research on perioperative use of methadone for analgesia & acute pain management.

Historically…METHADONE, the beginning -- German scientists synthesized methadone during World War II because of a shortage of morphine.Although chemically unlike morphine or heroin, methadone produces many of the same effects. Introduced into the United States in 1947 as an analgesic (Dolophine), Methadone is primarily used today for the treatment of narcotic addiction. The effects of methadone are longer-lasting than those of morphine-based drugs. Methadone's effects can last up to 24 hours, thereby permitting administration only once a day [as in heroin detoxification and maintenance programs].

What is Methadone?…the pharmacodynamics

A synthetic opioid agonist at the mu opioid receptor.Mu receptors produce the most profound analgesia

It has antagonistic activity at the NMDAreceptor

This counteracts opioid tolerance in experimental models of pain, possibly explaining the lesser escalation of dosage required in patients treated with methadone compared with morphineThis also results in increased efficacy against hyperalgesia andmay explain methadone’s greater effectiveness against neuropathic and other chronic pain states not responsive to other therapies

Manfredi& Houde, 2003Toombs & Kral, 2005

Methadone is a racemic mixture containing both an L-isomer and D-isomer: -the l-isomer is responsible for the drug's analgesic effects and is 8 to 50 times more potent than the D isomer . -the d-isomer exhibits significantly less analgesic action and lacks respiratory depression activity and addiction liability, but it does have antitussive effects.

Activation of the μ receptor by an agonist such as methadone causes:

analgesiasedation decreased respiration euphoriareduced BP, HR pruritisnauseamiosis &decreased bowel motility

Some of these effects, such as sedation, euphoria and decreased respiration, tend to disappear with continued use as tolerance develops.

Analgesia, miosis and reduced bowel motility tend to persist; little tolerance develops to these effects.

Stimulation of μ1-receptors blocks (supraspinal) pain while stimulation of μ2-receptor causes respiratory depression and constipation

What is Methadone?…the pharmacodynamics

-binds to mu, kappa and delta opioid receptors producing analgesia as well as usual opioid side effects.-inhibits reuptake of serotonin and norepinephrine (which are typical TCA actions).-is also an antagonist of NMDA receptors which can help prevent central sensitization and reduce opioid tolerance.

Toombs, 2006

What is Methadone?…the pharmacokinetics

Onset: 10-20 minPeak: 1-2 hrsDuration:

3-6 hrs with single dosing8-12 hrs with repeated dosing

Vd: 2-6 L/kg, highly lipophilicMetabolism: hepatic, no active metabolites

What is Methadone?…the pharmacokinetics

Highly protein bound; however tissue bindingpredominates over binding to plasma proteins [accumulation of the drug occurs in these tissues with repeated dosing], ie.maintains plasma conc.Half-life elimination: 8-59 hrs. [avg = 22hrs].

Prolonged with alkaline pHDecreased during pregnancyShorter in children than adults

Excretion: urine<10% as unchanged drugIncreased with urine pH <6

Indications of methadone treatment for pain states

Cost $$$

Neuropathic painMorphine allergyPain refractory to other opioidsUncontrolled painLow level of side effects

Application of Perioperative Methadone use in Anesthesia:

A Case Study--

Case Study--Patient Presentation:60 yo male, inpatientPulmonologist ASA 2No Prior Charts/RecordsHt: 71 in/Wt: 72 kgAllg: INHMeds:

ZantacDecadronMorphine PCA

PMH:+PPD s/p inhAsthma [rare symptoms]

PSxH-no anesthetic problemsRt C6-C7 foramenotomy 1987Left L4-L5 diskectomy 1989

Pre-op VS: 97.9 -72 -13; 126/72

MP 1 limited cervical extensionMET > 4

Chief ComplaintIncreased low back pain, right leg pain & weakness [4/5]Acute right foot drop- determined to be improvingL4-L5 stenosis/spondylosisRight L4-L5 radiculopathyPatient described this presentation as:

“much like mirror image of 16 years ago”

http://www.hughston.com/hha/a_12_1_1.htm http://www.acay.com.au/~mkrause/LBP.htm

Scheduled Procedure:Planned procedure: L4 laminectomy, L4-L5 PLIF, L4-L5 Monarch PSF

http://www.augustaortho.com/

Plan of Care : as proposed and discussed with CRNA and MDA

IV’s x2 [18g &16g]A-lineT&S/Cell saverInductionPositioning MaintenanceEmergence

*

*

PACU Record

Postoperative evaluation:PACU/DOSVerbalized comfortDenied pain Scaled pain as“0” of 0-10 using the Numerical Rating pain Scale

GMSF/POD#1PCA morphine “ barely using”Ambulating w/assist

Patients’ comments postop:

Pt reported “ I never felt so comfortable without feeling ‘clouded’ after surgery”

Inquired about “bridging with methadone” and how wonderful it worked for him

Methadone & It’s Use in Anesthesia

When to use methadone?It has been suggested that methadone is suitable as a first-line opioid in selected patients when slow onset and long duration of action are advantageous.

Methadone Guidelines for Pain. (2004).

When to use methadone in anesthesia?In a double-blind randomized study measuring postop pain:

30 Patients undergoing elective abdominal hysterectomies, age <60yrs randomized into 2 groups:

Morphine n=15Methadone n=15

ASA 1 or 2No opioids for minimum 24 hrs preopNo psychiatric hx or h/o drug abuseUsed 0-10 pain scale 0.25mg/kg of study drug given at inductionFurther 3 to 4.5 mg of assigned opioid was given in PACU q15min until pt was pain free for >30min.

VS/LOC measured q min x10min then q5min

Chui,P.T. and Gin,T. Anesthesia and Intensive Care (1992)20(1), 46-51. Double-Blind Randomized Trial Comparing Postoperative Analgesia After Perioperative Loading Doses of Methadone or Morphine.

Use of Perioperative Methadone…The Results:

Each group with 15pts of similar age and body weight– homogeneous samplesPts in the methadone group requested fewer doses of supplementary opioids than the morphine group [p<0.001].10 of 15 pts [67%] in the methadone did not require further parenteral opioid while all pts in the morphine group required at least 2 further doses of morphinePain scores were similar in both groups at time of discharge from the PACU however, Pain scores in the methadone group declinedsubsequently and the scores remained low for the 48hr study periodThe morphine group had a higher total pain score for the 48hr study period (p<0.001) despite having receiving more supplementary doses of morphine.

Chui,P.T. and Gin,T. Anesthesia and Intensive Care (1992)20(1), 46-51. Double-Blind Randomized Trial Comparing Postoperative Analgesia After Perioperative Loading Doses of Methadone or Morphine.

When to use methadone in anesthesia?In a double-blind randomized study measuring postop pain:

20 patients, ASA 1 or 2, undergoing surgery involving upper abdominal incision (all surgical procedures lasted for at least 60 min) randomly allocated to one of two treatment groups:

methadone (n=10) or morphine (n=10)

Gourlay, GK., Willis, R.J., & Lamberty, J. Anesthesiology (1986). 64(3): 322-327. A Double-blind Comparison of the efficacy of methadone and morphine in postoperative pain control.

Use of Perioperative Methadone….Patients were given a 20 mg intraoperative opioid dose ten minutes after induction 5 mg IV increments of opioid from precoded syringes were given for pain reported in the recovery and/or surgical units. (Each patient was administered only one opioid for the duration of the study (60h). Scheduled measurements of postop pain were estimated by the linear visual analogue pain scale; blood samples were concurrently measured for methadone concentrations



Use of Perioperative Methadone….The Results:

No significant differences in the patient groups

No significant difference in the amount of methadone (8 +/- 6.3mg, range 0-20 mg) or morphine (9 +/- 9 mg, range 0-25mg) administered in the recovery room to provide initial pain relief.

There was a highly significant (p<0.01) difference in the mean duration of pain relief between the methadone (20.7 +/- 20.2 h) and the morphine (6.3 +/- 3.0 h) group.The duration of pain relief ranged from 5.5 to 58 h in the methadone group and from 1.6 to 11.4 h in the morphine treatment group.

. Gourlay, GK., Willis, R.J., & Lamberty, J. Anesthesiology (1986). 64(3): 322-327. A Double-blind Comparison of the efficacy of methadone and morphine in postoperative pain control.

Summary & Analysis of Postop DosingResults provide further evidence in support of a prolonged duration of pain relief with methadoneSignificantly less (p<0.001) methadone (11.5 +/- 8.5 mg) compared with morphine (41 +/-14.1 mg) was administered in the surgical ward.The significant difference was also apparent when considering the total opioid required for pain relief.


Gourlay, Geoffrey K., Wilson, Perter R., & Glynn, Christopher J. Anesthesiology (1982)57: 6, pp 458-467 Pharmacodynamics and pharmacokinetics of methadone during the perioperative period.

Pharmacodynamics and Pharmacokinetics of Methadone During the Perioperative PeriodAnesthesiology. (1982). 57(6): 458-467.Gourlay,K.G., Wilson,P.R. & Glynn,J.C

Dosing of IV Methadone for moderate to severe pain:

Optimal dose initiation and titration strategies for the treatment of pain have not been determinedMethadone is most safely initiated and titrated using small initial doses and gradual dose adjustmentsIn opioid naïve patients, the usual IV methadone starting dose is 2.5 to 10 mg every 8 to 12 hrs, slowly titrated to effect

Dosing of IV methadone for moderate to severe pain: some studies reported:

Lower-than-expected doses of IV methadone were needed for pain relief in cancer patients unrelieved by morphine and hydromorphone. When IV hydromorphone dosage could not be further increased due to sedation effects, cancer patients found relief of pain with IV methadone at 2.6% to 3.8% of the calculated equianalgesic dose of hydromorphone

Manfredi et al, 1997

However,“For various reasons, there is significant individual variability in patient response to methadone, making initiation of therapy and rotation to methadone from other opioids, at times unpredictable.As such, it does require some special care and knowledge in its use. The use of ‘equivalency tables’ to calculate a dose of methadone is unreliable and should be avoided.”

methadone guidelines for pain, Nov 2004

Exactly!

‘Start low, go slow’In some patients [elderly/infirm], very small doses of methadone may be quite effective and generally better toleratedRemember! A dose can always be increasedDue to gradual accumulation to a steady state, methadone’s effectiveness as an analgesic may improve gradually after a dose increase, for up to four to five days

‘Start low, go slow’Most methadone related deaths [as studied on MMT pts] occur in the first week of therapy, as a result of accumulation, emphasizing the importance of careful monitoring during the initiation of therapy.Methadone blood levels continue to rise abut 5 days after starting treatment or raising a previously stable dose.Death by accumulated toxicity may result from increasing a dose before the full effect of the current dose is known.

methadone guidelines for pain, Nov 2004

of importance with dosing:When determining the initial IV dose of methadone, the following should be considered:

Total daily dosePotencyCharacteristics of the opioid the patient had been taking, if any

Patients degree of opioid toleranceAge, condition & medical status of the patientConcurrent medicationsType, severity and expected duration of painAcceptable balance between pain control and adverse effects

Caution with dosingIndividualizeEquianalgesia not always equalNote acute vs chronic dosing & management information

Considerations with MethadoneHigh interindividual variability

Equianalgesic doses vary widely person-to-person and day-to-day/week-to-week in same person

Long half-lifeVarying level of plasma binding proteinAge, gender, weight (large distribution reservoir)Other medicationsTime from start of treatment (auto-induction)/slow onset

Stoetlting & Hillier, 2006

Methadone warnings:May prolong QT interval

Use caution with severe volume depletion

Effects on respiration last longer than its analgesia effects

Decrease dose with renal impairment

Caution in patients with liver disease

Equianalgesia not always equalDrug IM POFentanyl 0.15 mg 0.12 mg SLHydrocodone 20mgHydromorphone 2 mg 8 mgLevorphanol 2 mg 4 mgMeperdine 100 mg 100 mgMethadone 10 mg 10 mgMorphine 10 mg 30 mgOxycodone 20 mg

DoseEquivalents for opioid analgesics in opioid-naive adults and children>= 50 kg body weight

Opioid agonist

Oral Parenteral Dosing interval

Morphine 30 mg 10 mg Q 3-4h

Hydromorphone 7.5 mg 1.5 mg Q 3-4h

Meperidine 300 mg 100 mg Q 2-3h

Methadone 20 mg 10 mg Q 6-8h

Fentanyl Variable ** -------- Transdermal patches q3days

Equianalgesia not always equal

Ogle, K, Lovell, K. & Zaluski, H.(2000) Pain relief for terminally ill patients.:http://www.echt.chm.msu.edu/blockiii/pain/BlockIIIcorecompetency/equianalgestic_table.htm

Equianalgesia not always equal

https://www.hoparx.org/HOPA2006/nesbit.pdf

Equianalgesia not always equal…

Parental morphine to IV methadone conversion for chronic administration for patients with chronic pain:

Total daily baseline IV morphine dose

Est daily IV methadone requirement % of total daily morphine dose

10 to 30 mg 40% to 66%

30 to 50 mg 27% to 66%

50 to 100 mg 22% to 55%

100 to 200 mg 15% to 34%

200 to 500 mg 10% to 20%

Suggested safe & effective starting doses when rotating patients from other IV opioids to IV methadone with PCA

InitialOpioid

Basal New Opioid

Basal Demand ClinicianActivatedbolus

morphine 10 mg methadone 1 mg 1 mg 5 mg

dilaudid 1.5 mg methadone 0.3 mg 0.3 mg 5 mg

fentanyl 250 µg methadone 1.25 mg 1.25 mg 5 mg

Manfredi & Houde, 2003

Methadone drug interactions:

Toombs & Kral, 2005

Estimated monthly drug costsComparative cost analysis of commonly prescribed opioids:

Toombs & Kral, 2005

So, why don’t we use methadone?Some comments:

“for heroin addicts”“stigma”“never used it” “don’t know it”“Never heard of it being used in anesthesia”“government regulations & MMT”“I don’t know, it’s a great drug”“I don’t think the hospital has it.”

‘Anesthesia and Methadone’:Review of the Literature

Research, publications & information on

the use of methadone in Anesthesia is dated and challenging to find.


Biddle, Chuck, CRNA, PhD. (2005). The long term use of opiates for pain control: Laputa revisited? AANA Journal 73:1, 62-69.Bowdle, T. Andrew, MD, PhD, Even, Aaron, MD., Shen, Danny D., & Swardstrom, Meghan. (2004). Methadone for the induction of anesthesia: plasma histamine concentration, arterial blood pressure and heart rate. Anesthesia Analgesia 98:6, pp1692-1697.Chestnut, David, MD.(2005) Efficacy and safety if epidural opioids for postoperative analgesia. Anesthesiology 102:1, 221-223.Chui, P.T. & Gin, T. (1992) A double-blind randomized trial comparing postoperative analgesia after perioperative loading doses of methadone and morphine. Anaesthesia Intensive Care 20:1, 46-51.Coll, AnnMarie, Ameen, Jamal R.M. & Mead, Donna. (2004).Postoperative pain assessment tools in day surgery: literature review. Journal of Advanced Nursing 46:2. 124-133.Cowan, David T, While, Alison, & Griffiths, Peter (2004) Use of strong opioids for non-cancer pain in the community: a case study. British Journal of Community Nursing 9:2, 53-58.College of Physicians and surgeons of Ontario. (2004). Methadone Guidelines for Pain. pp1-58.Fredheim, Olav Magnus S., Kaasa, Stein, Dale, Ola, Klepstad, Pal, Landro, Nils Ingre & Borchgrevink, Petter, C. (2006) Opioid switching from oral slow release morphine to oral methadone may improve pain control in chronic non-malignant pain: a nine-month follow-up study. Palliative medicine 20: 35-41.


Gourlay, K. Gourlay, B. PharmD, PhD, Willis, Richard, J. & Lamberty, John. (1986). A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology 64: 322-327.Gourlay, Geoffrey, K., Willis, Richard, J, & Wilson, Peter R. (1984). Postoperative pain controlwith methadone: influence of supplementary methadone doses and blood concentration – response relationships. Anesthesiology 61: 1, pp19-26Gourlay, Geoffrey K., Wilson, Perter R., & Glynn, Christopher J. (1982). Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology 57: 6, pp 458-467.Griffe, Julie, Coyne, Patrick, & Coyle, Nessa. (2006) Difficult cases in pain management: use of methadone in a multifactorial approach. Clinical Journal of Oncology Nursing 10:1, 45-49http://www.anesthesia forum.com/Methadone.htm. (2006). Withdrawn 03/26/2006. Methadone, the IV form. Mak, Peter H.K., Tsui, Siu T., & Jacobus Ng, K.F. (2002). Long-term therapy of chronic non-malignant pain with potent opioids in an active police officer. Canadian Journal of Anesthesia, 49:6, pp 575-578.Mamie, C. Berstein, M., Morabia, A., Klopfenstein, C.E., Sloutskis, D. & Forster. A (2004 ) Are there reliable predictors of postoperative pain. Acta Anesthesiol Scand 48: pp 234- 242.Manfredi, Paolo L MD & Houde, Raymond W. MD. (2003). Prescribing methadone, a unique analgesic. J of Supportive Oncology 1:3 pp 216-220.


Mercadente, Sebastiano, Casuccio, Alessandra & Calderone, Luciano. (1999). Rapid switching from morphine to methadone in cancer patients with poor response to morphine. Journal of clinical oncology, v17:i10. pp 3307-3312.Micromedix® Healthcare series. Drugdex drug evaluations: Methadone. 3/23/2006.Mitra, Sukanya MD. & Sinatra, Raymond MD (2004)Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology 101:1, pp 212-227.Palmer, Stephen, PhD, Giesecke, Martin, MD, Body, Simon, C., Sherman, Stanton K. MD, Fox, Amanda A, MD, & Collard, Charles, D. MD. (2005). Review article: Phamacogenetics of Anesthetic and analgesic agents. Anesthesiology 102; 663-71Peng, Philip W.H., Tumber, Paul S MD, & Gourlay, Douglas MD. (2005). Review article. Perioperative pain management of patients on methadone therapy. Can J of Anesthesia 52:5 513-523 Porter, E.J.B., McQuay, H.J., Bullingham, L.,Weir, Allen, M.C., and Moore, R.A. (1983),Comparison of effects of intraoperative and postoperative methadone: acute tolerance to the postoperative dose? British Journal of Anesthesia 55:4, pp325-332.Prieto-Alvarez, Pilar MD PhD, Tello-Galindo, Isabel MD, Cuenca-Pena, Jesus MD, Rull-Bartomeu, MD,PhD & Gomar-Sancho, Carmen MD, PhD. (2002). Continuous epidural infusion of racemic methadone results in effective postoperative analgesia and low plasma concentrations. Canadian Journal of Anesthesia 49:1, pp 25-31.Richlin,David M., MD & Reuben, Scott, MD.(1991). Postoperative pain control with methadone following lower abdominal surgery. J Clinical Anesthesia 3: Mar/Apr. pp112-116


Shimoyama, Naohito, Shimoyama, Megumi, Elliott, Kathryn J. & Inturrisi, Charles, E. (1997). D-Methadone is antinociceptive in the rat formalin test. The Journal of Pharmacology and Experimental Therpaeutics 283: 2, pp648-652.Strassels, Scott A, McNicol, Ewan & Suleman, Rosy. (2005). Postoperative pain management, a practical review Part 1. American J of Health System Pharmacology 62:15 pp 1904-1916.Strassels, Scott A, McNicol, Ewan & Suleman, Rosy. (2005).Postoperative pain management: a practical review Part 2. American J of Health System Pharmacology 62:15 pp 2019- 2026.Toombs, James D. MD & Kral Lee, PharmD. (2005). Methadone treatment for pain states. American Family Physician 71:7, 1353-1358.Wootton, Margaret (2004) Morphine is not the only analgesic in palliative care: literature review. Journal of Advanced Nursing 45(5), 527-532.Yoram, Shir MD, Rosen,Gila RN, Zeldin,Alexander MD, & Davidson, Elyad M MD (2001).Methadone is safe for treating hospitalized patients with severe pain. Can J Anesthesia 48:11 pp 1109-1113

However, ongoing research pending:Clinical trialsIncrease the research in anesthesia to provide for evidence based practice.

On the horizon…Methadone Clinical Trials

Methadone - Comparison of A Single Dose Combination of Methadone and Morphine With Morphine Alone for Treating Post-Operative Pain - This study is currently recruiting patients (Current: 08 Jun 2006) Methadone - Phase III Randomized Controlled Study of Morphine and Nortriptyline in the Management of Postherpetic Neuralgia - This study has been completed (Current: 08 Jun 2006) Methadone - Project Pain - 1 - This study is currently recruiting patients (Current: 08 Jun 2006) Methadone - Sublingual Methadone for the Management of Cancer Breakthrough Pain - This study is currently recruiting patients (Current: 08 Jun 2006) Methadone - Switching From Morphine to Methadone. A Clinical, Pharmacological and Pharmacogenetic Study - This study is currently recruiting patients (Current: 08 Jun 2006) Methadone - Treatment of Chronic Pain After Spinal Cord Injury (SCI) or Amputation - This study is no longer recruiting patients (Current: 08 Jun 2006)

http://clinicaltrials.gov

In Summary…Methadone & It’s Use in Anesthesia

Pros & Cons of pharmacokinetics & pharmacodynamicsBenefits of prolonged duration of pain control with less frequent dosingLess drug required;w/ better pain control & less side effectsdifficult drug to manage because:

has long and variable half-life, with slow onset of analgesiait takes 2 weeks to reach steady stateaccumulation can result in prolonged sedation and difficulty in managing fluctuations in pain

More cost effectiveMay be more effective than other opioids for neuropathic pain because of NMDA receptor activity

ReferencesChui, P.T. & Gin, T. (1992) A double-blind randomized trial comparing postoperative analgesia after perioperative loading doses of methadone and morphine. Anaesthesia Intensive Care 20:1, 46-51.Fishman, S.M., Wilsey B, Mahajn G. (2002). Methadone reincarnated: Novel clinical applications and related concerns. Pain Medicine 3:339-348. Gourlay, K., Gourlay, B., Willis, Richard, J. & Lamberty, John. (1986). A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology 64: 322-327.Gourlay, Geoffrey K., Wilson, Perter R., & Glynn, Christopher J. (1982). Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology 57: 6, pp 458-467http://clinicaltrials.gov/ct/show/NCT00142519www.acay.com.au/~mkrause/LBP.htmhttp://www.anesthesiaforum.com/Methadone.htmhttp://www.cpso.on.ca/Publications/pain.htm. (2000). Evidenced based recommendations for medical management of chronic non-malignant pain. Reference guide for physicians.

Referenceswww.hughston.com/hha/a_12_1_1.htmhttp://www.mascc.org/ktml2/images/uploads/16thSymposiumProceedings/contents/papers/ss12-1/data/downloads/ss12-1.pdf#searchopioidpharmacokineticshttp://www.ucsf.edu/pain/orientation/opioid%20analgesics.PDF#searchopioidpharmacokineticshttp://www.vasg.org/opioid_analgesics.htmManfredi, P.L., Borsook, D., Chandler, S.W.& Payne, R. (1997). Intravenous methadone for cancer pain unrelieved by morphine andhydromorphone: clinical observations. Pain(70); 99-101.Manfredi, P.L. & Houde, R.W. (2003).Prescribing methadone, a unique analgesia.Journal of Supportive Oncology:(1)216-220.

ReferencesMethadone Guidelines for Pain. (2004).facilitated by the College of Physicians and Surgeons of Ontario.Micromedex®healthcare series drugdex drug evaluations: methadoneOgle, K, Lovell, K. & Zaluski, H. (2000). Pain relief for terminally ill patients retrieved from: http://www.echt.chm.msu.edu/blockiii/pain/BlockIIIcorecompetency/equianalgestic_table.htmStoelting, R.K. & Hillier, S.C.(2006). Pharmacology and physiology in anesthetic practice: Opioid agonists and antagonists. Lippincott, Williams & Wilkins, Philadelphia, PA.Toombs, J.D. (2006) Methadone dosing for chronic pain in Ambulatory Patients. A Clinicians Perspective.retrieved form Pain Treatment Topics : http://www.Pain-Topics.comToombs, J.D. & Kral, L.A. (2005). Methadone treatment for pain states. American Family Physician(71)7, 1353-1358

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Methadone and It’s Use in Anesthesia · The morphine group had a higher total pain score for the 48hr study period (p

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