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Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 6 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 16

Perioperative Management Considerations for Patients on Methadone and Buprenorphine
Emily Coleman, RN, CCRN, SRNA
Affiliation:
Texas Christian University School of Nurse Anesthesia

Funding/Conflict of Interest Disclosure: 
None

KEYWORDS:  Methadone; buprenorphine; mu opioid receptor; multimodal analgesia; medication-assistant treatments; anesthesia 
management

Abstract
A 52-year-old female with a history of chronic pain and methadone therapy was scheduled for spinal cord stimulator 
removal. Patients with chronic pain or opioid use disorders (OUD) are often managed with prescriptions or medica-
tion-assisted treatments (MAT) involving methadone and buprenorphine. Existing case studies, expert opinions, and 
clinical practice advisories recommend continuation of methadone and buprenorphine perioperatively to avoid regimen 
disruptions and drug level fluctuations. Most recommendations are also in agreement for providers to implement multi-
modal analgesia and incorporate regional/neuraxial anesthesia when appropriate.  Abrupt discontinuation of methadone 
can result in opioid withdrawal or place the patient at risk for relapse. Buprenorphine is a partial μOR agonist with high 
receptor binding affinity and slow dissociation properties. Perioperative buprenorphine management varies widely, but 
many guidelines and protocols recommend continuing buprenorphine preoperatively. 

INTRODUCTION
One hundred million people in the United States live with chronic pain and around two million people suffer from substance abuse 
disorder related to opioids and heroin.1-3 Deaths due to drug overdose have increased four-fold between 1999 and 2017.4 Many 
patients undergoing surgery and anesthesia have chronic pain or OUD, requiring providers to understand and address the complexity 
of medications such as methadone and buprenorphine. Lack of awareness and ineffective pain management for these patients can re-
sult in higher opioid use from inadequate pain control, exacerbation of withdrawal or relapse, and increased risk of cardiac, respiratory, 
and neurological depression.1-9

AEJ



Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 6 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 17

CASE SUMMARY
A 52-year-old, 146 kg, 167 cm, female presented for spinal cord 
stimulator removal. The patient’s past medical history includ-
ed asthma, mitral valve prolapse without any current issues or 
symptoms, arthritis, obesity with a body mass index (BMI) of 52, 
depression, anxiety, and chronic pain. The patient’s past surgical 
history included stomach surgery, gallbladder surgery, abdominal 
hysterectomy, tubal ligation, right knee surgery, nerve anastomosis 
of left arm, and spinal cord stimulator placement. In 2010 the 
patient was shot multiple times in the left arm and right knee, 
which led to chronic pain and placement of spinal cord stimulator 
for pain management in 2014. The patient denied any previ-
ous complications with anesthesia. An anesthetic record from 
2017 had noted the patient to be a difficult airway. Intubation 
was obtained after three attempts, with successful placement of 
endotracheal tube facilitated by utilization of Glidescope vid-
eo laryngoscopy, cricoid pressure, and Eschmann tracheal tube 
introducer. Her outpatient medication list included albuterol, 
alprazolam, gabapentin, methadone, venlafaxine, cyclobenzaprine, 
and topiramate. Allergies to erythromycin and penicillin, which 
both cause respiratory distress for the patient, were reviewed 
and confirmed. Laboratory results from pre-surgery testing were 
unremarkable. Pre-anesthetic evaluation was performed, and the 
patient reported to have discontinued methadone intake about 6 
months ago. The patient was classified as physical status III.   
Upon arrival to the operating room, the patient maintained 
supine position on stretcher. Physiologic monitors were applied, 
including pulse oximeter, noninvasive blood pressure (BP) cuff, 
electrocardiogram (ECG) monitoring, and capnography. Pre-in-
duction vital signs were heart rate (HR) 76 beats per minute, BP 
165/71 mm Hg, oxygen saturation (SpO2)100%, respiratory rate 
of 13, and temperature of 36.2°C. The patient was preoxygen-
ated via face mask with 100% FiO2 at 15 L/min. Induction was 
initiated once patient’s end-tidal oxygen concentration levels were 
above 85%. General anesthesia was induced intravenously with 
fentanyl 100 mcg, lidocaine 50 mg, propofol 200 mg, rocuronium 
50 mg, and ketamine 30 mg. Due to a previous anesthesia record 
from 2017 indicating difficult airway, Glidescope video laryn-
goscopy was utilized, grade I view of vocal cords was obtained, 
and the airway was secured with a 7.0 mm endotracheal tube. 
Placement confirmation was verified through bilateral breath 
sounds, positive end tidal carbon dioxide capnography waveform, 
and symmetrical chest wall movement. Sevoflurane 0.6-2.1% was 
used as anesthetic maintenance agent with oxygen at 1 L/min and 
air at 1 L/min. Initial vital signs post-intubation was HR of 106 
beats per min, BP of 162/134, SpO2 of 100%. Patient was then 
placed in prone position on a Wilson frame for surgery. 
Local anesthesia infiltration was performed by surgical team 
with wound closure. Patient was repositioned to supine position 
on the stretcher. Intravenous medications including ketamine 20 
mg, ondansetron 4 mg, methocarbamol 1 g, neostigmine 3 mg, 
and glycopyrrolate 0.4 mg were administered during emergence 
of anesthesia. Train-of-four monitor revealed 4/4 twitches with 
sustained tetany for 5 seconds. Spontaneous respirations and 
adequate tidal volumes were maintained. After oropharyngeal 
suctioning and extubation criteria were met, the endotracheal 
tube was removed. Oxygen at 4 L/min via facemask was applied 
as patient was transported to post-anesthesia care unit (PACU). 

Post-procedure vital signs were HR 75 beats per minute, BP 140/70 
mm Hg, SpO2 100%, respiratory rate of 16, and temperature of 
36.1°C. No anesthesia or surgical complications were noted. Patient 
was discharged from PACU within the same day. 

DISCUSSION
The opioid abuse pandemic and increasing numbers of patients 
with chronic pain presents a multitude of challenges periopera-
tively and little has been studied to provide high quality evidence 
as guidance to optimal pain management.1-6 Patients with chronic 
pain or OUD are vulnerable and at risk for ineffective pain 
management, marginalization, opioid withdrawal, and relapse. 
Existing MAT for chronic pain or OUD involves opioid agonists 
such as methadone, partial agonists such as buprenorphine, or 
antagonists such as naloxone. Methadone, buprenorphine, and 
naloxone will complicate the patient’s care perioperatively, due to 
their pharmacological profile and interpatient variabilities.1-10

Figure 1. Effect of OUD medications on opioid receptors15

Pharmacology of Methadone 
Methadone, a synthetic opioid, is a racemic mixture of the 
R-methadone and S-methadone enantiomer. R-methadone enan-
tiomer is a full μOR agonist, while the S-methadone enantiomer 
is an N-methyl-D-aspartate (NMDA) antagonist and prevents 
serotonin and norepinephrine reuptake.1,2,4-7 Recent studies sug-
gest that methadone has a higher potency than previously report-
ed, with a median conversion ratio of methadone to morphine 
of about 7.75 to 1.7 Administration of methadone orally reaches 
peak plasma drug concentration between two to three hours, with 
an average half-life of 23 hours.6 The biphasic pattern of elimi-
nation observed in methadone is the reason for its effectiveness 



in MAT for chronic pain or OUD. The alpha-elimination phase 
of methadone correlates with its duration of analgesia, which is 
between 6 to 12 hours. The beta-elimination phase lasts between 
30 to 60 hours with sub-analgesic effects, which is sufficient in 
preventing withdrawal symptoms.7 Pain management providers 
often prescribe methadone to be taken three to four times daily in 
correspondence to its analgesic and elimination properties.4-8

Methadone is commonly prescribed for patients that abuse heroin 
due to its μOR affinity and prolonged half-life. Therefore, chronic 
methadone can attenuate the euphoric effects from heroin 
to decrease dependence and abuse. Methadone has also been 
utilized in acute pain management in anticipation of significant 
postoperative pain.4,6 

Perioperative Management of Patients on Methadone 
The pharmacological profile of methadone including its potent 
analgesic effects and extensive half-life are important factors to 
consider perioperatively.1,2,4-7 Life threatening complications such 
as accumulated toxicity, opioid withdrawal, and overdose can 
occur in terms of methadone abuse or inadequate management.7 
Current literature reports a single 40 mg dose of oral methadone 
could result in death, especially in opioid naïve patients. Therefore, 
providers will also need to be aware of an increased risk of car-
diac, respiratory, and neurological depression in patients that are 
receiving opioids.1 It is imperative to perform a thorough preoper-
ative assessment to gather information on the patient’s history of 
methadone therapy. Details of methadone dosing, level of com-
pliance, and patient’s previous experiences with anesthesia are all 
necessary information to form an anesthetic plan.1,2,4-7 Patients that 
are diverting their methadone or ingesting other illicit drugs may 
require further testing such as urine drug screen, electrocardiogram, 
and liver and renal function tests.5,7

Current recommendations advise patients on methadone to adhere 
to their regimen and continue their normal dose on the day of their 
surgical procedure.1,2,4-7 Patient compliance prevents drug level 
fluctuations and possible withdrawals.5,7 Prescribed daily dose of 
methadone is inadequate in managing acute pain, therefore provid-
ers should consider multimodal pain management strategies.1,2,4-7 
Opioid-free anesthesia is preferred especially in patients with a 
history of opioid addiction.1 Consider incorporating agents such 
as volatile anesthetics, ketamine, benzodiazepines, acetaminophen, 
non-steroidal anti-inflammatory drugs (NSAIDs), gabapentinoids, 
alpha-2 adrenergic receptor agonists, local anesthetics, and region-
al/neuraxial anesthesia.1,2,6,7 There is a lack of research and data on 
the preferred opioid of choice in treating patients with chronic 
pain or OUD. The goals of administering subanesthetic doses 
of ketamine, wound infiltration with local anesthesia, and other 
nonopioid interventions are to decrease opioid requirements while 
improving pain scores.11 
Postoperatively, patient’s maintenance methadone dose should be 
continued as soon as possible.1,2,4-7 If opioids are required for break-
through pain, some articles recommend short-acting opioids.1,2 
Studies have reported opioid-dependent patients require four times 
more narcotics than opioid naïve patients.11 In anticipation of 
moderate to severe pain postoperatively, patient controlled analge-
sia (PCA) may be appropriate.1,6 Lastly, it is important to note that 
partial opioid agonists such as buprenorphine and butorphanol will 
precipitate withdrawal symptoms and should be avoided.2

The patient presented in the case study had a history of metha-
done consumption due to chronic pain that resulted from gunshot 
inflicted tissue and nerve damage on her left arm. Although the 
patient reported discontinuing methadone therapy, multimodal 
analgesia and administration of short-acting opioids were still im-
plemented. Local anesthesia was also applied by the surgical team 
intraoperatively. The patient had minimal to no pain in PACU 
and was discharged within the same day. 

Pharmacology of Buprenorphine 
Buprenorphine is another common medication approved by the 
U.S. Food and Drug Administration (FDA) for chronic pain or 
OUD. Buprenorphine has unique pharmacological features as a 
partial agonist at the μOR and an antagonist of the kappa opioid 
receptors.3-6 As a partial agonist, buprenorphine has a ceiling 
effect that minimizes additional opioid effects despite repeated 
or increased dosing.2-4,8-10 Due to the ceiling effect, buprenor-
phine causes less respiratory depression and has a lower abuse 
potential compared to methadone.2-4,6-9 Despite being a partial 
agonist, buprenorphine has a high affinity for the μOR, therefore 
it will compete with and displace other full opioid agonists.2,3,8-10 

Buprenorphine is an effective treatment for OUD as it relieves 
withdrawal symptoms through its partial opioid agonist effects 
if the μOR were not occupied. If buprenorphine is administered 
or ingested during an euphoric state under the influence of full 
agonists such as heroin or other opioids, buprenorphine will dis-
place the full agonist and trigger precipitated withdrawal due to a 
decrease in agonist effect.2,8,9

Buprenorphine is available through various routes including 
sublingual, buccal, transdermal, and injectable formulations.2,4,9 

Buprenorphine can be administered alone or in combination 
with an opioid antagonist such as naloxone. The combination of 
buprenorphine and naloxone decreases the abuse potential due to 
their bioavailability when administered sublingually compared to 
parentally. Sublingually, buprenorphine has a high bioavailability 
as it avoids first pass metabolism while naloxone is poorly ab-
sorbed. If the combination of the two drugs are injected parenter-
ally, both agents are highly bioavailable which allows naloxone to 
become active and counteract the euphoric effects.2-4,6,8,9

Buprenorphine and Mu Opioid Receptor Affinities 

Buprenorphine has features such as high μOR affinity, slow disso-
ciation from the receptor, and prolonged duration with a half-life 
of 25-60 hours.2,4,10 The majority of opioid analgesic and anesthet-
ic agents bind to the μOR, which causes supraspinal analgesia. 
Additionally, μOR agonists are responsible for euphoric effects, 
sedation, respiratory depression, decreased intestinal motility, and 
physical dependence.12 Receptor binding affinity is measured by 
the equilibrium dissociation constant (Ki).10,12,13 Opioids with low 
Ki values have stronger binding affinity at the μOR. The Ki value 
of buprenorphine is 0.216 nM, exceeded only by sufentanil with 
a Ki value of 0.138 nM (Table).10,12,13 A case series recommended 
utilization of opioids such as hydromorphone or sufentanil with 
Ki values closer to buprenorphine to achieve better analgesia.10

Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 6 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 18



Figure 2. Summary of opioid receptor signaling14

Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 6 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 19

Table. Mu Opioid Receptor Affinity Measured by the Equilibri-
um Dissociation Constant (Ki)12-13

Drug Ki (nM)
Hydrocodone 41.58
Oxycodone 25.87
Alfentanil 7.391
Methadone 3.378
Nalbuphine 2.118
Morphine 1.168
Fentanyl 1.346
Butorphanol 0.7622
Oxymorphone 0.4055
Hydromorphone 0.3654
Buprenorphine 0.2157
Sufentanil 0.1380

Perioperative Management of Patients on Buprenorphine 

As a partial agonist with strong μOR affinity, buprenorphine 
attenuates the effect of other μOR agonists. The ceiling effect 
of buprenorphine decreases risks of respiratory depression and 
overdose but presents a challenge in surgical analgesia.9 Therefore, 
patients taking buprenorphine are at high risk for ineffective pain 
management leading to severe postoperative pain.2,9 Inadequate 
pain relief may cause longer postoperative recovery times, in-
creased anxiety levels, and provoke drug-seeking behaviors.9 

There is a lack of high-quality research and evidence regarding 
perioperative management of patients on buprenorphine. Most 
guidelines and protocols are derived from expert opinion, case 
studies, and clinical practice advisories.3,4,11 Preoperatively, current 
literature suggest anesthesia providers to perform comprehensive 
assessments to obtain patients’ history of buprenorphine ther-
apy and other pertinent information. It is important to review 
patient’s compliance level with prescriptions, pain management 
history, and previous experiences with anesthesia.2,5,11 Diagnostic 
testing and toxicology screening should also be considered for ob-
jective information.2,3,10 There are conflicting views and concepts 
regarding preoperative continuation of buprenorphine.2-4,11 Some 
reports recommend discontinuing buprenorphine two to five 
days prior to surgery to ensure μOR availability.2 Other sources 
noted there is a lack of evidence that discontinuing buprenor-
phine would prevent relapse episodes.3 Furthermore, patients 
that discontinued buprenorphine were found to have a significant 
increase in opioid requirements postoperatively.4

Continuing buprenorphine preoperatively is advocated in some 
literature to maintain stable serum drug levels and to avoid 
exacerbations of withdrawal or relapse.2-4,11 Optimal perioperative 
pain management should incorporate non-opioid analgesia as a 
priority.2-4,9,11 Providers could include ketamine, acetaminophen, 
NSAIDs, gabapentinoids, and alpha-2 adrenergic receptor ago-
nists.3 Local anesthesia infiltration and regional/neuraxial anes-
thesia should be utilized where possible.2-4,9-11 Initiating full μOR 
agonists may be appropriate when inadequate analgesia persists 
with multimodal management.2-4,11 Clinicians need to be aware 
that successful pain management with patients on buprenorphine 
often requires increased doses of opioids.2-4,9-11 Due to the high 
μOR receptor binding affinity of buprenorphine, other potent 
full agonists with high Ki values may be required to overcome the 



receptor.10 Hydromorphone and sufentanil are examples of μOR 
agonists with Ki values similar to buprenorphine.3,10,11 
SUMMARY
While methadone and buprenorphine are the leading medica-
tions for treating chronic pain and OUD, optimal perioperative 
management of these medications have not been well established. 
Due to the unique pharmacological profiles of methadone and 
buprenorphine, it is imperative to perform thorough preoperative 
evaluations to assess for patient compliance to their prescribed 
medications, and to discuss concerns of diversion, or possible 

withdrawal and relapses perioperatively. Current guidelines 
and protocols recommend patients to continue their medica-
tion regimen unless instructed differently by their prescribing 
provider.1-11 Optimal perioperative management of patients on 
methadone may include short-acting opioid agonists, multimodal 
analgesia, regional/neuraxial anesthesia, and other non-opioid 
interventions.1,2,4-7 Optimal perioperative management of patients 
on buprenorphine may include multimodal analgesia, regional/
neuraxial anesthesia, and opioid agonists with similar μOR bind-
ing affinity to buprenorphine.2-4,9-11

REFERENCES
1. Cornett EM, Kline RJ, Robichaux SL, et al. Comprehensive perioperative management considerations in patients taking 

methadone. Curr Pain Headache Rep. 2019;23(7):49. doi:10.1007/s11916-019-0783-z.
2. Ward EN, Quaye AN, Wilens TE. Opioid use disorders: perioperative management of a special population. Anesth Analg. 

2018;127(2):539–547. doi:10.1213/ANE.0000000000003477
3. Goel A, Azargive S, Weissman JS, et al. Perioperative Pain and Addiction Interdisciplinary Network (PAIN) clinical 

practice advisory for perioperative management of buprenorphine: results of a modified Delphi process. Br J Anaesth. 
2019;123(2):e333-e342. doi:10.1016/j.bja.2019.03.044.

4. Scholzen E, Zeng AM, Schroeder KM. Perioperative management and analgesia for patients taking buprenorphine and other 
forms of medication-assisted treatment for substance abuse disorders. Adv Anesth. 2019;37:65-86. doi:10.1016/j.aan.2019.08.002.

5. Mitra S, Sinatra RS. Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology. 2004;101(1):212-
227. 

6. Vadivelu N, Mitra S, Kaye AD, Urman RD. Perioperative analgesia and challenges in the drug-addicted and drug-dependent 
patient. Best Pract Res Clin Anaesthesiol. 2014;28(1):91-101. doi:10.1016/j.bpa.2014.02.003.

7. Peng PWH, Tumber PS, Gourlay D. Review article: perioperative pain management of patients on methadone therapy. Can J 
Anaesth. 2005;52(5):513-523. 

8. Whelan PJ, Remski K. Buprenorphine vs methadone treatment: A review of evidence in both developed and developing worlds. J 
Neurosci Rural Pract. 2012;3(1):45–50. doi:10.4103/0976-3147.91934

9. Roberts DM, Meyer-Witting M. High-dose buprenorphine: perioperative precautions and management strategies. Anaesth Intens 
Care. 2005;33(1):17-25. 

10. Leighton BL, Crock LW. Case series of successful postoperative pain management in buprenorphine maintenance therapy 
patients. Anesth Analg. 2017;125(5):1779–1783. doi:10.1213/ANE.0000000000002498

11. Coluzzi F, Bifulco F, Cuomo A, et al. The challenge of perioperative pain management in opioid-tolerant patients. Ther Clin Risk 
Manag. 2017;13:1163–1173. Published 2017 Sep 5. doi:10.2147/TCRM.S141332

12. Volpe DA, McMahon Tobin GA, Mellon RD, et al. Uniform assessment and ranking of opioid μ receptor binding constants for 
selected opioid drugs. Regul Toxicol Pharmacol. 2011;59(3):385-390. doi:10.1016/j.yrtph.2010.12.007.

13. Ellis CR, Kruhlak NL, Kim MT, Hawkins EG, Stavitskaya L. Predicting opioid receptor binding affinity of pharmacologically 
unclassified designer substances using molecular docking. Plos One. 2018;13(5):e0197734. doi:10.1371/journal.pone.0197734.

14. Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 
2011;115(6):1363-1381. doi:10.1097/ALN.0b013e318238bba6.

15. Medication-assisted treatment improves outcomes for patients with opioid use disorder. the pew charitable trusts. https://www.
pewtrusts.org/en/research-and-analysis/fact-sheets/2016/11/medication-assisted-treatment-improves-outcomes-for-patients-
with-opioid-use-disorder. Published November 26, 2016. Accessed March 26, 2020. 

About the Author: 
Emily Coleman is completing the final year of obtaining a Doctor of Nursing Practice at Texas Christian University. Coleman 
graduated from The University of Texas at Austin with a Bachelor of Science in Nursing. Coleman was one of twelve accepted into 
the undergraduate Nursing Honors Program and completed a secondary analysis as her honor’s thesis. Before beginning her doctoral 
education, Coleman was a medical intensive care nurse at UT Southwestern. Her background in pulmonary and critical care medicine 
involved caring for patients with pulmonary hypertension, sepsis, renal failure, respiratory failure, and more.  Her current professional 
interests include pharmacology, regional anesthesia, obstetric anesthesia, and pain management.

Educated Hand Publishing LLC 
“The Science Behind the Art” 
Volume 8 - No. 6 2020 

 Anesthesia eJournal - Online
ISSN 2333-2611

Page 20

https://www.pewtrusts.org/en/research-and-analysis/fact-sheets/2016/11/medication-assisted-treatment-improves-outcomes-for-patients-with-opioid-use-disorder.
https://www.pewtrusts.org/en/research-and-analysis/fact-sheets/2016/11/medication-assisted-treatment-improves-outcomes-for-patients-with-opioid-use-disorder.
https://www.pewtrusts.org/en/research-and-analysis/fact-sheets/2016/11/medication-assisted-treatment-improves-outcomes-for-patients-with-opioid-use-disorder.

