1. A Comparison of Postoperative Opioid Requirements and Effectiveness in
Methadone-maintained and Buprenorphine-maintained Patients
Thankyou for inviting me to present the results of our recent investigation which compares post operative opioid requirements and effectiveness in methadone-maintained and buprenorphine-maintained patients, an audit conducted within the department of Anaesthesia and Pain medicine at the Royal Adelaide Hospital in South Australia.
Dr. R. A. Russell Department of Anaesthesia, Pain Medicine & Hyperbaric Medicine Royal Adelaide Hospital 1

2. Opioid Substitution Therapy
Australian patients on methadone-maintenance therapy (MMT) or buprenorphine-maintenance therapy (BMT) :
1998: 24,657
2009: 43,445
The number of Australians maintained on opioid substitution therapy has doubled over the past 10 years. Figures provided by the Australian Institute of Health and Welfare show that almost 44,000 patients were enrolled in opioid substitution programs in As the number of patients maintained on opioid substitution therapy increase we will see parallel increases in the number requiring treatment for acute pain.
AIHW 2009

3. Buprenorphine Opioid Pharmacology
Partial mu-agonist & kappa-antagonist
Full mu-agonist at analgesic doses
Anti-hyperalgesic properties
High opioid receptor affinity
Slow offset kinetics
Buprenorphine has been characterised as a partial mu-agonist and kappa-antagonist although at analgesic dosages behaves clinically as a full mu-agonist and may have anti-hyperalgesic properties. Of concern has been the fact that buprenorphine has a high opioid receptor affinity and slow offset kinetics, leading to concerns that the resultant blockade could interfere with effective acute pain management using other full mu opioid agonists.
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Various opinions have been expressed as to whether the drug should be ceased before surgery.

4. Partial opioid blockade ?
Buprenorphine
Opioid Pharmacology
Partial mu-agonist & kappa-antagonist
Full mu-agonist at analgesic doses
Anti-hyperalgesic properties
High opioid receptor affinity
Slow offset kinetics
Partial opioid blockade ?
To cease or not to cease perioperatively?

5. BMT Clinical Guidelines
Acute Pain Management: Scientific Evidence
‘…There appears to be little problem if buprenorphine is continued and acute pain managed with the combination of a short acting pure opioid agonist as well as other multimodal analgesic strategies...’
The ANZCA acute pain document suggests in practice there appears to be little problem if buprenorphine is continued and it doesn’t interfere with use of other short acting pure opioid agonists.
NHMRC Acute Pain Management: Scientific Evidence 3e (2010)

6. BMT Clinical Guidelines
ASRA E-News – January, 2011
For patients undergoing elective surgery with moderate-severe post-operative pain:
Discontinue BMT 3-7 days prior to surgery.
Transition to other opioids (e.g. methadone) and non-opioid pain medications.
In contrast as recently as January 2011, a statement in the American Society for regional anaesthesia and pain medicine newsletter suggested that for patients undergoing elective surgery; buprenorphine should be discontinued electively 3-7 days prior to surgery and substituted for a full agonist opioid such as methadone.

7. Study Overview Method Inclusion Criteria Exclusion Criteria
Audit of APS data ( )
Inclusion Criteria
MMT & BMT patients
PCA (IV) post-operatively
Exclusion Criteria
Regional analgesia with PCA
Collaborators
Dr Kris Usher & A/Prof Pam Macintyre
Given advice from experts has varied, we decided to examine data compiled from our APS database in an audit of postoperative pain management of patients normally maintained on methadone and buprenorphine. Specifically we examined patients who received parenteral opioid via PCA post operatively and excluded those small number of patients who received additonal regional analgesia.

8. Results Total patients = 51 BMT = 22 MMT = 29 BUP cont = 11
ceased = 11
MMT = 29
METH cont = 22
METH ceased = 7
As seen , we collected data from 51 patients. 22 were maintained on buprenorphine although this was ceased in half of them. In contrast, 29 patients were maintained on methadone and this was more likely than buprenorphine to be continued peri-operatively. Indeed, methadone was ceased in only 7 patients.

9. Results BUP cont. BUP ceased METH cont. METH ceased Age (yrs)
40.2  0.4
38.9  10.8
39.0  7.2
38.8  7.9
Alcohol
27%
18%
14%
Cannabis 9%
23%
BZD
36%
50%
29%
Looking at patient demographics the average patient age was similar across all groups. Perhaps unsurprisingly, a substantial number of patients reported poly-substance use (with alcohol and benzodiazepines being most prevalent). In total 68% of patients reported alcohol dependence or use of an additional illicit substance.

10. 1st 24hr PCA Requirements Morphine equivalents (mg) 281 ± 129 mg
METH
(ALL)
METH
(CONT)
METH
(CEASED)
BUP
(ALL)
BUP
(CONT)
BUP
(CEASED) 10

11. 1st 24hr PCA Requirements Morphine equivalents (mg) 281 ± 129 mg
1st 24 hour PCA requirements are shown here. We demonstrate that both groups of methadone maintained and buprenorphine maintained patients had higher opioid requirements than would be expected in an opioid naive population. For example patients where methadone was ceased had an average requirement of 281mg with large variation. Patients where buprenorphine was ceased had an average requirement of 245mg again with large variation. As is seen clearly, opioid requirements were significantly higher for patients in whom methadone or buprenorphine was ceased.
196 ± mg
155 ± mg
245 ± mg
METH
(ALL)
METH
(CONT)
METH
(CEASED)
BUP
(ALL)
BUP
(CONT)
BUP
(CEASED) 11

12. Results BUP cont. BUP ceased METH cont. METH ceased Pain – rest
4.1  1.9
4.7  2.2
4.6 2.0
5.4  2.2
Pain – movt.
6.6  1.7
6.9  2.6
7.5 1.7
8.1  2.5
N & V (Req. Rx)
36.4%
27.3%
22.7%
32.9%
Sedn Score = 2*
18.2%
28.6%
Pain was scored between Pain scores were higher than are typically reported in the opioid naive population although as I will show you in a minute not unlike pain scores recorded in opioid-tolerant patients. Pain scores appeared to be higher if buprenorphine or methadone was ceased peri-operatively.
Nausea and vomiting requiring antiemetic therapy occurred in ¼ to 1/3 of all patients and appeared independent of buprenorphine or methadone cessation. This is simmilar to most studies reporting post operative nausea and vomitting.
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Of significance however was the incidence of sedation mandating reduction of PCA opioid bolus dosage. In patients maintained on buprenorphine or methadone using our sedation scoring system a sedation score of 2 (meaning easily roused but unable to stay awake and taken to indicate early respiratory depression) was seen in 18%. Whilst this is similar to the incidence seen across our database for opioid tolerant patients it remains significantly higher than the overall incidence of 1.68%. Cessation of buprenorphine and methadone peri-operatively was associated with the highest incidence of sedation requiring intervention although it should be noted that severe respiratory depression was not seen in any patients.
* Overall incidence sedn score of 2 in all RAH APS patients = 1.68%

13. Results BUP cont. BUP ceased METH cont. METH ceased Pain – rest
4.1  1.9
4.7  2.2
4.6 2.0
5.4  2.2
Pain – movt.
6.6  1.7
6.9  2.6
7.5 1.7
8.1  2.5
N & V (Req. Rx)
36.4%
27.3%
22.7%
32.9%
Sedn Score = 2*
18.2%
28.6%
* Overall incidence sedn score of 2 in all RAH APS patients = 1.68%

14. Results BUP cont. BUP ceased METH cont. METH ceased Paracetamol 100%
Ketamine
27%
54%
71%
Days PCA
2.2  1.4
4.6  3.0
2.7  1.6
6.0  2.8
Days APS
3.0  1.7
5.9  3.9
4.0  2.5
8.7  3.4
All patients received adjuvant simple analgesia including paracetamol. Low-dose ketamine infusions (4-8mg / hr) were significantly more likely to be prescribed in patients whom drugs had been ceased.
Those patients in whom the drugs were ceased required PCA analgesia for twice as many days and were under the care of the APS for a longer time.

15. Opioid-tolerant Patients
Royal Adelaide Hospital 1998 (n = 214, PCA)
Opioid-tolerant
1st 24 h PCA Morphine
171 mg
Pain Score - Rest (median) 6
Pain Score - Movt. (median) 8
Sedation score 2 or 3
14%
Our results compare closely with an earlier unpublished audit of all opioid-tolerant patient within the APS database. It should be noted that the above figure summarised data for all patients receiving chronic opioid analgesia including for chronic pain syndromes and malignancy). We see the opioid requirements and pain scores in this group are similar with an elevated risk of sedation requiring intervention or rescue.

16. Opioid-naive vs. Opioid-Tolerant
Rapp et. al (n = 149, PCA)
Opioid-naive
Opioid-tolerant
1st 24 h PCA Morphine
47  32 mg
136  69 mg
Pain Score - Rest 3 5
Pain Score - Movt. 7 8
Sedation score 2 or 3
19%
50.3%
This is also similar to the results reported by Rapp in 1995 in a retrospective study. They looked at 149 opioid tolerant patients with chronic pain and malignancy, and those with an addiction to opioids. They compared them with a matched group of opioid naieve patients. As you can see the opioid tollerant group required three times more opioid with higher pain scores and significantly higher incidence of over sedation.

17. Conclusions
Patients maintained on methadone & buprenorphine substitution therapy:
High 1st 24 hour PCA opioid requirements
Large inter-patient variability
Higher pain scores
Increased incidence of sedation
In conclusion, we demonstrate that patients maintained on methadone and buprenorphine substitution therapy have high PCA opioid requirements with a large inter-patient variability and are more likely to report high pain scores. Compared with our opioid naieve patients they are also more prone to over-sedation whilst receiving PCA. However, there were no differences between methadone and buprenorphine patients.
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Perhaps counter-intuitively, PCA doses and pain scores were higher when buprenorphine and methadone were ceased. This is clearly contrary to any belief that continuation of buprenorphine will interfere with analgesia using other opioids.

18. Conclusions
Patients maintained on methadone & buprenorphine substitution therapy:
High 1st 24 hour PCA opioid requirements
Large inter-patient variability
Higher pain scores
Increased incidence of sedation
PCA doses and pain scores are higher if BMT and MMT are ceased perioperatively

19. Conclusions Cessation of BMT & MMT Higher opioid requirements
Longer duration of PCA therapy
Requirement for more intensive APS management
Indeed cessation of buprenorphine and methadone peri-operatively is associated with higher opioid requirements, longer duration of PCA therapy and the requirement for more intensive APS management.
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In summary Our data demonstrates that buprenorphine can infact be continued peri operatively without adversely effecting pain relief using pure agonist opioids.
To answer the conculsion first raised – Should buprenorphine be ceased perioperatively, we would recommend it is continued and this reflects our current practice.
Thankyou.

20. Conclusions Cessation of BMT & MMT
Higher opioid requirements
Longer duration of PCA therapy
Requirement for more intensive APS management
Buprenorphine can be continued perioperatively without adversely effecting pain relief using pure agonist opioids.