Toward a systematic approach to opioid rotation

Figures & data

Table 1 Characteristics of clinical trials/case series describing opioid rotation

Study	Design	Participants	Rotation method	Outcomes
Hallett and Chalkiadis^Citation128	Case report	Postsurgical pediatric patient, on opioids uncontrolled	Rotation to hydromorphone and ketamine commenced	Pain score 24 h after opioid rotation
McDonnell et al^Citation42	Randomized clinical trial	44 pediatric chronic pain of noncancer origin patients on PCA morphine	Rotation to PCA hydromorphone in seven patients with pain not controlled with PCA morphine	PCA ratio of patient demands to pump deliveries
Oldenmenger et al^Citation43	Prospective observational study	104 chronic pain of cancer origin patients uncontrolled with existing opioid analgesic	Rotation to IV hydromorphone due to poor pain control (n=61), intolerable AEs (n=43)	Pain control (pain intensity; duration of failure-free treatment)
Ostgathe et al^Citation44	Retrospective chart review	52 inpatient palliative care patients	Titrate oral levo-methadone, maintain single dose after 72 h titration, increase dosing interval to q8h (plus PRN q3h)	Pain intensity (NRS); amount of dosing after 72 h number maintained single dose until AEs
Sato et al^Citation129	Case series	Two patients undergoing pain management in the home-care setting	Rotation from fentanyl to continuous IV morphine at less than the equivalent dose based on conversion table	Risk of delay in detection of adverse reactions to opioid overdose
Webster and Fine^Citation130	Case report	Patient undergoing pain management using a new paradigm	Rotation based on a slow decrease in the dose of previous oxycodone ER and slow titration of the dose of hydromorphone ER with IR opioid to control BTP	Pain control AEs
Weiner et al^Citation131	Case report	Patient with central pain syndrome uncontrolled by PO morphine and hydrocodone with acetaminophen	Step 1: unsuccessful rotation from morphine to transdermal fentanyl Step 2: successful rotation to transdermal buprenorphine 60 μg/h q7d	Self-reported pain control (VAS) Performance status
Hanaoka et al^Citation48	Prospective observational study	66 chronic pain of cancer origin patients with uncontrolled moderate to severe pain	Rotation from existing opioid to fentanyl patch (1-day formulation) based on dose level of preceding opioid analgesic	Pain control AEs
Kawano et al^Citation49	Prospective observational study	45 chronic pain of cancer origin patients	Rotation from morphine IV to transdermal fentanyl patch	Equivalent doses and conversion ratios for daily delivered dose of morphine injection and fentanyl patch
Korkmazsky et al^Citation41	Prospective observational study	Patients with chronic pain of noncancer origin receiving morphine or oxycodone for ≥3 months	Rotation to oral oxymorphone ER with IV-PCA oxymorphone for 24 h PRN and oxymorphone IR based on total 24-h IV-PCA oxymorphone use	AEs Patient PGIC and BPI Treatment satisfaction Change in oxymorphone dose
Gatti et al^Citation40	Multicenter, open-label prospective trial	326 patients with chronic pain of cancer or noncancer origin not controlled by SR opioid alone:  Morphine <320 mg  Oxycodone <120 mg  Hydromorphone <64 mg  Fentanyl <125 μg  Buprenorphine <140 mg or in combination with analgesics	Step 1: Rotation to oral IR morphine 5 or 10 mg q4h to reduce pain score to ≤50% of baseline; Step 2: rotation from IR morphine to a different SR opioid (no guidelines for opioid choice)	Pain intensity (NRS score) Daily episodes of BTP (BPI scale) AEs Treatment compliance
Parsons et al^Citation46	Retrospective chart review	189 chronic pain of cancer origin patients	Rotation to methadone (n=89) in an outpatient setting	Methadone rotation Success rate Reasons for opioid rotation Mean daily methadone dose Demographic and clinical characteristics, pain scores, and opioid AEs
Benítez-Rosario et al^Citation25	Retrospective analysis	54 severe pain of cancer origin patients uncontrolled by morphine	Opioid rotation: Methadone initial dose calculated using MMEDR of 5:1 Dose calculated at a ratio of 10:1 in patients receiving >600 mg/d morphine who were anxious, depressed, or delirious and had a history of rapid increase in morphine dose or low morphine clearance	MMEDR at day 10 with explanatory factors in multiple linear regression model
Leppert^Citation50	Prospective observational study	21 chronic pain of cancer origin patients: morphine (n=11), transdermal fentanyl (n=4), morphine, ketamine and transdermal fentanyl (n=1), tramadol (n=1), pethidine (n=1), or morphine with ketamine (n=3)	Rotation from previous opioid using stop-start approach to oral methadone; equivalent DDOM to DDOMET were 4:1(DDOM to 100 mg), 6:1 (101–300 mg), 12:1 (>1,000 mg); with BTP treated with methadone^Citation132 and other agents	Methadone analgesia AEs Effectiveness of DDOM to DDOMET dose calculation method
Matsuyama et al^Citation133	Case report	Chronic pain of cancer origin patient uncontrolled with oxycodone ER	Rotation to matrix-type transdermal fentanyl	Pain relief Relief of severe constipation
Cheema et al^Citation38	Prospective observational study	49 chronic pain of cancer origin patients	Rotation from oxycodone to morphine (n=23, 47%) followed by a second (12%), third (3%), and fourth (2%) opioid rotation	Frequency of opioid rotation Indications for opioid rotation: inadequate analgesia, AEs, cost, organ failure, NP, route and dosing convenience
Davies et al^Citation51	Retrospective analysis	17 chronic pain of cancer origin pediatric patients with uncontrolled pain from primary opioid	Rotation to methadone from primary opioid based on morphine equivalent dose (range, 1:2 to 60:1)	AEs Improvement in analgesia
Likar et al^Citation134	Case series	Four chronic pain of noncancer origin patients with uncontrolled pain with existing opioids	Rotation to transdermal buprenorphine	Opioid conversion ratio Pain relief
Narabayashi et al^Citation30	Multicenter, open-label dose-titration study	25 cancer patients with inadequate pain control or intolerable adverse events on morphine	Rotation to oxycodone CR using a 3:2 oxycodone:morphine ratio	Pain on a 4-point categorical rating scale: 0= no pain, 3= severe pain Oxycodone dose stability AEs
Okon and George^Citation135	Case report	Pain of cancer origin patient with uncontrolled pain with increasing doses of opioids	Rotation from IV morphine to transdermal fentanyl with dose increase to 200 μg/h for persistent severe pain	Pain control Resolution of symptoms
Peng et al^Citation39	Retrospective chart review	100 chronic pain of noncancer origin patients	Rotation to methadone from previous opioid analgesic based on morphine-equivalent dose before methadone therapy	Methadone stabilized dose Consistency of conversion ratio Duration of therapy Pain intensity NVRS Use of concomitant agents AEs
Vorobeychik et al^Citation136	Case report	Chronic pain of cancer origin patient with pain uncontrolled by escalating doses of oxycodone, morphine, and hydromorphone	Rotation to methadone following 40%–50% reduction in dose of hydromorphone	Pain intensity (VAS) Mental status
Walker et al^Citation47	Retrospective chart review	39 chronic pain of cancer origin patients with pain poorly controlled by existing opioid	Rotation to oral and IV methadone based on oral MEDD of previous opioid	Dose ratio for oral and IV methadone to oral MEDD Latency of achieving stabilized dose
Akiyama et al^Citation137	Case series	22 severe chronic pain of cancer origin patients	Rotation from morphine to transdermal fentanyl patch	Transition to home-care setting Control of pain, analgesic effect, and AEs
Braiteh et al^Citation52	Retrospective chart review	61 chronic pain of cancer origin patients	Neuroleptics (n=33, 54%); opioid rotation (not specified; n=30, 49%)	Reasons for mobile team consultation: pain (n=47, 77%) and delirium (n=10, 16%) Improvement in pain at 24 and 72 h
Clemens and Klaschik^Citation53	Retrospective analysis	81 chronic pain of cancer origin patients pretreated with transdermal fentanyl	Rotation from transdermal fentanyl to oral morphine (n=33) or oral hydromorphone (n=44)	Decrease in pain score (NRS at rest/exertion); tolerability of oral morphine or hydromorphone
Freye et al^Citation37	Prospective observational study	42 chronic pain of cancer and noncancer origin patients with pain uncontrolled with high-dose morphine (120–>240 mg/d)	Rotation from morphine to buprenorphine (≥52.5 mg/h)	Pain relief Patient satisfaction and QOL Severity of adverse drug reactions
Hale et al^Citation27	Double-blind, placebo-controlled study	250 chronic low back pain patients with pain uncontrolled by hydrocodone, oxycodone, morphine, methadone, fentanyl, codeine,a or propoxyphene	Conversion to oxymorphone ER based on calculated equianalgesic doses; titration was based on response every 3–7 d	Successful titration VAS Pain Intensity AEs
Riley et al^Citation12	Prospective, observational, controlled study	186 cancer pain patients treated with morphine; non-responders rotated to oxycodone CR, fentanyl, or methadone	Not specified	Subjective assessment of pain control AEs
Wirz et al^Citation56	Prospective, observational, study	50 chronic pain of cancer origin patients in an outpatient setting	Rotation from oral morphine, transdermal fentanyl, tramadol, oxycodone, and sublingual buprenorphine to oral hydromorphone ER (MED, 108.9–137.6 mg/d) without modifying concomitant analgesics	Pain intensity (NRS) Gastrointestinal symptoms Relief of insomnia
Morita et al^Citation29	Retrospective analysis	20 chronic pain of cancer origin patients with morphine-induced delirium	Morphine switched to equivalent fentanyl (transdermal or parenteral) using a conversion ratio (morphine 10 mg = fentanyl 159 mg)	Severity of delirium (MDAS) Pain (STAS) Performance status
Moryl et al^Citation138	Retrospective analysis	20 opioid-refractory chronic pain of cancer origin patients with uncontrolled pain and terminal delirium	Rotation to equianalgesic dose of methadone based on previous morphine-equivalent dose (n=7); 2 patients restarted on morphine IV; 1 patient restarted on acetaminophen + oxycodone	Pain control (NRS) Severity of delirium (MDAS) Alertness and cognitive status
Muller-Busch et al^Citation139	Multicenter, prospective observational study	412 palliative care patients receiving opioids	Rotation from oral to parenteral morphine (n=106) or to other long-acting opioids (n=49)	AEs and efficacy Correlation between baseline opioid use and rotation frequency
Shinjo and Okada^Citation140	Case report	Chronic pain of cancer origin patient with pain uncontrolled by escalating doses of transdermal fentanyl	Rotation to transdermal fentanyl (150 μg/h) in combination with oral morphine SR (360 mg/d)	Pain control
Zimmermann et al^Citation141	Case series	Two chronic pain of cancer origin patients with pain uncontrolled by escalating doses of parenteral hydromorphone	Rotation to a smaller than predicted dose of oral methadone	Pain control AEs
Benítez-Rosario et al^Citation45	Prospective observational study	17 cancer patients receiving transdermal fentanyl	Rotation to oral methadone: Step 1: transdermal fentanyl: oral morphine (1:100) Step 2: oral morphine: oral methadone (5:1 or 10:1)	Correlation between previous fentanyl dose and final methadone dose; change in pain intensity after rotation; use of daily rescue doses
Drake et al^Citation36	Retrospective analysis	22 chronic pain of cancer origin children with pain uncontrolled with morphine	Rotations from morphine to fentanyl favored in 20 of 30 (67%) rotations Rotation from fentanyl to hydromorphone favored in 6 of 30 (20%) rotations	Pain intensity AEs MED after rotation
Kato et al^Citation54	Prospective observational study	144 chronic pain of cancer origin patients with difficulty tolerating oral morphine	Rotation from oral morphine to transdermal fentanyl (efficacy ratio, 1:78)	Conversion ratio of oral morphine to transdermal fentanyl Pain control Reduction in morphine AEs Use of rescue analgesia
Schriek^Citation142	Case series	Three advanced chronic pain of cancer origin patients	Rotation to transdermal buprenorphine after failure of step I or step II opioids	Pain control Tolerability
Grilo et al^Citation57	Case series	67 rheumatologic chronic pain of noncancer patients with pain uncontrolled with morphine	Opioid rotation:   Oral SR morphine to transdermal fentanyl  Oral SR morphine to oral SR hydromorphone  Other rotations	Change in pain severity (VAS)
Moryl et al^Citation35	Prospective case series	13 chronic pain of cancer origin patients with pain uncontrolled with methadone (6–80 mg/h)	First opioid rotation to hydromorphone (initial dose: 1–6 mg/h); morphine (60 mg/h); fentanyl (250–1,500 μg/h); levorphanol (4–5 mg/h) Dose of second opioid before switch to methadone: hydromorphone, 7.9–40 mg/h; morphine, 75 mg/h; fentanyl, 125–3,240 μg/h; levorphanol, 5–30 mg/h	Change in VAS pain Sedation score AEs Patient satisfaction Reason for opioid rotation Factors limiting dose escalation Reasons for discontinuation of second opioid
Mercadante et al^Citation28	Prospective observational study	52 cancer patients receiving morphine	Rotated to methadone using a 1:4, 1:8, or 1:12 methadone:morphine dosing ratio. Lower ratios were used for patients on higher morphine doses	Change in VAS pain AEs
Kloke et al^Citation34	Retrospective chart review	273 chronic pain of cancer origin patients	Rotation to morphine, fentanyl, methadone, or buprenorphine	Frequency of opioid rotation Influence of adjuvants Risk factors for opioid rotation Reasons for not recommending rotation
Quang-Cantagrel et al^Citation55	Retrospective chart review	86 chronic pain of noncancer origin patients with pain poorly controlled by long-acting opioid	Treated sequentially with morphine, oxycodone, methadone, or transdermal fentanyl patch until effective, well-tolerated opioid found	Adequate pain response (≥50% reduction in pain) AEs all <30 on a 100-point scale
Thomsen et al^Citation33	Retrospective analysis	88 chronic pain of noncancer origin patients in outpatient setting	31 rotations from LAO to different LAO:  Morphine to methadone (n=12)  Ketobemidone to morphine (n=7)  Morphine to oxycodone (n=4)  Ketobemidone to oxycodone (n=3)  Oxycodone to methadone (n=3)  Ketobemidone to methadone (n=2) 28 rotations from SAO to LAO:  Ketobemidone to methadone (n=9)  Ketobemidone to morphine (n=7)  Tramadol to morphine (n=8)  Tramadol to methadone (n=2)  Tramadol to ketobemidone (n=2)	Reason for rotation Changes in dose after rotation Pain control (anecdotal)
Daeninck and Bruera^Citation143	Case series	Four cancer patients with history of laxative use: Case 1: breast cancer and history of visceral and neuropathic pain Case 2: prostate cancer and history of bone and neuropathic pain Case 3: NHL and bilateral neuropathic leg pain Case 4: pancreatic cancer and postprandial back pain	Opioid rotations: Case 1: from hydromorphone twice daily to methadone Case 2: from hydromorphone and carbamazepine to methadone Case 3: from transdermal fentanyl patch and hydromorphone for BTP plus benzodiazepine to methadone Case 4: from morphine to hydromorphone to methadone	Change in constipation and laxative use
Gagnon et al^Citation26	Observational study	63 severe chronic pain of cancer origin patients with pain uncontrolled with more than two different strong opioids (ie, morphine, hydromorphone)	Rotation from morphine SC or hydromorphone SC to oxycodone SC	Analgesic effect on ESAS Tolerability of rotations to oxycodone Cost of oxycodone SC
Bruera et al^Citation144	Retrospective chart review	113 chronic pain of cancer origin patients with pain uncontrolled with morphine (n=36) and hydromorphone (n=77)	Opioid rotation:  Hydromorphone SC to methadone PO/rectal  Morphine PO/SC to hydromorphone SC/PO  Hydromorphone PO/SC to morphine PO/SC	Reasons for opioid rotation: change in analgesic dose and pain intensity (VAS) after rotation
Vigano et al^Citation145	Case report	Neuropathic pain patient with pain uncontrolled with PO morphine	First rotation:  Morphine to hydromorphone, with dose increase: from 140 mg/d (MEDD=280)  PO to 210 mg/d (MEDD=1050) SC; plus amitriptyline (25–50 mg PO), dexamethasone (6 mg PO, three times daily), metoclopramide SC 10 mg q4h, cisapride 10 mg PO four times daily Second rotation:  Hydromorphone to methadone 90 mg PO (MEDD=36); major increase at 4 months (≤1,200 mg/24 h (MEDD=480) Third rotation:  Methadone to hydromorphone (600–900 mg/24 h MEDD=3,000–4,950)	Improvement in functional performance (ESAS) Assessment of pain (VAS) and cognitive function (MMSQ)
de Stoutz et al^Citation31	Retrospective chart review	191 chronic pain of cancer origin patients	First opioid rotation for each patient: from morphine, hydromorphone, methadone, diamorphine, and fentanyl to new opioid (morphine, hydromorphone, methadone, diamorphine, and fentanyl)	MEDD, patient-assessed symptoms (VAS and ESAS), and cognitive function (MMSQ) before and after opioid rotation

a Note: Codeine Contin is not available in the United States.

Abbreviations: AE, adverse event; BPI, Brief Pain Inventory; BTP, breakthrough pain; CR, controlled release; d, days; DDOM, daily dose of oral morphine; DDOMET, daily dose of oral methadone; ER, extended release; ESAS, Edmonton Symptom Assessment Scale; h, hours; IR, immediate release; IV, intravenous; LAO, long-acting opioid; MDAS, Memorial Delirium Assessment Scale; MED, morphine equivalent dose; MEDD, morphine equivalent daily dose; MMEDR, morphine/methadone dose ratio; MMSQ, Mini-Mental Status Questionnaire; n, number of patients; NHL, non-Hodgkin lymphoma; NP, neuropathic pain; NRS, Numerical Rating Scale; NVRS, Numerical Verbal Rating Score; PCA, patient-controlled analgesia; PGIC, patient’s global impression of change; PO, by mouth; PRN, as needed; QOL, quality of life; SAO, short-acting opioid; SC, subcutaneous; SR, slow release; STAS, Schedule for Team Assessment Scale; VAS, Visual Analog Scale; q7d, every 7 days; q3h, every 3 hours; q4h, every 4 hours; q8h, every 8 hours.

Table 2 Selected patient factors influencing opioid efficacy and/or tolerability

Opioids	Age	Sex	Ethnicity	Hepatic impairment^Citation24	Renal impairment^Citation24	Cardiovascular/respiratory disease	Risk of abuse
Morphine	Clearance may be reduced in older patients	No effect	Chinese patients have higher clearance	Dose adjustments recommended	Dose adjustments recommended	Use with caution	Frequently abused
Hydrocodone	Caution recommended in older patients	No effect	No effect	May be formulated in combination with acetaminophen; liver function testing advised in patients with hepatic impairment	May be formulated in combination with acetylsalicylic acid; renal function testing advised in patients with renal impairment	Use with caution	Frequently abused
Oxycodone	Concentrations nominally higher in older patients	Concentrations ≈ 25% higher in women than in men	No effect	Dose adjustments recommended	Dose adjustments recommended	More respiratory depression than morphine or tramadol	TRF available
Buprenorphine	No dose adjustment necessary	No effect	No effect	Not evaluated	No effect	Use with caution	Recommended for patients with confirmed or suspected misuse/with daily supervised dispensing
Hydromorphone	No effect	Cmax 25% higher in men; AUC0–24 is the same in both sexes	No effect	Dose adjustments recommended	Dose adjustments recommended	Use with caution	Frequently abused
Oxymorphone	Steady-state concentrations ~40% higher in older patients	Concentrations the same in men and women after adjusting for body weight	No effect	Contraindicated in patients with moderate to severe hepatic impairment	Dose adjustments recommended	Use with caution	TRF available
Levorphanol	Dose adjustments may be required for older patients	No effect	No effect	Not evaluated	Not evaluated	Dose adjustments recommended	Frequently abused
Tapentadol	Dose adjustments recommended	No effect	No effect	Contraindicated in patients with severe hepatic impairment	Contraindicated in patients with severe renal impairment	Use with caution	TRF available
Fentanyl	Clearance may be reduced in older patients	No effect	No effect	Dose adjustment may not be necessary	Dose adjustment may not be necessary	Use with caution	Frequently abused
Methadone	Dose adjustments may be required for older patients	No effect	No effect	Dose adjustments recommended in patients with severe hepatic impairment	Dose adjustments recommended in patients with severe renal impairment	Avoid	Recommended for patients with confirmed or suspected misuse/with daily supervised dispensing

Note: Adapted from Mayo Clin Proc, 84/7, Smith HS, Opioid metabolism, 613–624, Copyright © 2009, with permission from Elsevier.²⁴

Abbreviations: AUC_0–24, area under the concentration versus time curve from time 0 to 24 hours; C_max, maximum plasma concentration; TRF, tamper-resistant formulation.

Table 3 Characteristics of commonly used opioids

Opioid	Receptor binding	Routes of administration	Metabolic pathway	Ceiling dose	Onset of effect	Duration of effect
Morphine	μ, κ (weak)	Oral tablet, oral liquid, intramuscular or subcutaneous, epidural or intrathecal, intravenous, rectal	Glucuronidation	None	NA	ER or IR
Hydrocodone	μ, κ	Oral	CYP2D6	Yes for combination products, no for pure hydrocodone	Rapid	ER or IR
Oxycodone	μ, κ (strong)	Oral, rectal	CYP3A4 CYP2D6	Yes for combination product, no for pure oxycodone	Rapid	ER or IR
Buprenorphine	μ (antagonist), κ (agonist, weak partial)	Transdermal, transmucosal	CYP3A4, glucuronidation	Yes	Slow	Long
Hydromorphone	μ, κ (weak), δ (weak)	Oral, intramuscular or subcutaneous, intravenous, rectal	Glucuronidation	None	N/A	ER or IR
Oxymorphone	μ	Oral, intravenous, rectal	Glucuronidation	None	N/A	ER or IR
Levorphanol	μ, κ, δ	Oral	Glucuronidation	6–12 mg/d	Rapid	Long
Tapentadol	μ, 5-HT, NE	Oral	Glucuronidation CYP2C9 (minor) CYP2C19 (minor)	500 mg/d	Slow	ER or IR
Fentanyl	μ, κ (weak)	Transdermal, transmucosal, intranasal, intravenous	CYP3A4	None	Very rapid (transmucosal, intravenous) Very slow (transdermal)	Very short Very long (transdermal)
Methadone	μ, κ (weak), δ (strong), NMDA	Oral	CYP3A4 CYP2B6 CYP2C8 CYP2C19 CYP2D6 CYP2C9	None	Slow	Long

Abbreviations: 5-HT, serotonin; CYP, cytochrome P450; d, day; ER, extended release; IR, immediate release; N/A, not applicable; NE, norepinephrine; NMDA, N-methyl-D-aspartate.

Table 4 Potential for DDIs associated with disruption of key cytochrome P450 enzymes

Opioid	Analgesic effects of DDIs
	Induction of CYP3A4	Inhibition of CYP3A4	Inhibition of CYP2D6
Morphinea	No likely clinical consequences	No likely clinical consequences	N/A
Hydrocodone	Potential increase in opioid effects; patient monitoring recommended	Potential decrease in opioid effects; patient monitoring recommended	N/A
Oxycodone	Decrease in opioid effects; avoid combination when possible	Increase in opioid effects (black box warning); avoid combination	Potential decrease in opioid effects
Oxymorphonea	N/A	N/A	N/A
Buprenorphine	Decrease in opioid effects	Increase in opioid effects	N/A
Levorphanola	N/A	N/A	N/A
Fentanyl	Decrease in opioid effects; avoid combination when possible	Increase in opioid effects (black box warning); avoid combination	N/A
Methadone	Decrease in opioid effects; avoid combination	Increase in opioid effects; avoid combination when possible	Increase in opioid effects; avoid combination

a Notes: Drugs metabolized primarily by UGT2B7 (Phase II) and not likely to be associated with significant DDIs caused by alterations to CYP3A4 and CYP2D6. For more information on Buprenorphine see McCance-Katz et al.¹⁴⁶ Copyright © 2011. Adapted from The American Journal of Managed Care. Overholser BR, Foster DR. Opioid pharmacokinetic drug-drug interactions. Am J Manag Care. 2011;17(suppl 11):S276–S287.¹⁴⁷

Abbreviations: CYP, cytochrome P450; DDIs, drug–drug interactions; N/A, not applicable.

Figure 1 Algorithm for initial patient assessment and initiation and rotation of opioid therapy.

Abbreviation: CYP, cytochrome P450.

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