Morphine with Dextromethorphan: Conversion from Other Opioid Analgesics

© U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(99)00130-X

S42 Journal of Pain and Symptom Management Vol. 19 No. 1(Suppl.) January 2000

Proceedings SupplementNMDA-Receptor Antagonists: Evolving Role in Analgesia

Morphine with Dextromethorphan: Conversion from Other Opioid Analgesics

Eric Chevlen, MD

St. Elizabeth Hospital, Youngstown, OH, USA

Abstract

MorphiDex

®

, a 1:1 combination of dextromethorphan and morphine, provides satisfactory pain control at a significantly lower morphine daily dose. To determine the appropriate conversion regimens from other oral or transdermal opioid analgesics to MorphiDex

®

(MS:DM), 592 patients with moderate to severe chronic pain requiring daily use of opioid analgesics were enrolled in this multicenter, open-label study. Patients were instructed to use MS:DM as needed to achieve satisfactory pain control. Overall, study patients took a significantly lower morphine daily dose (

P

5

0.0001), and a higher percentage (

P

5

0.0001) rated therapy with MS:DM as “very good” or “excellent” compared to their prestudy opioid. The mean daily dose of MS:DM remained level throughout a 10 month study extension period, suggesting that MS:DM may inhibit the development of tolerance to morphine. Most of the adverse events observed with MS:DM were those commonly reported with opioid therapy and were mild to moderate in severity. MS:DM appears safe and effective in treating moderate to severe chronic pain.

J Pain Symptom Manage 2000;19:S42–S49.

© U.S. Cancer Pain Relief Committee, 2000.

Key Words

Dextromethorphan, morphine, opioids, analgesia, chronic pain

Introduction

An opioid for the management of chronicpain, newly introduced to the medical marketplace, may be used in one of two ways. First, pa-tients who are opioid naive and who requireopioid therapy may start the new agent. Sec-ond, patients already receiving opioid therapymay have their therapy switched to the newmedication in an attempt to achieve betterpain control, fewer side effects, or both.

The research model for studying how well aparticular drug works for opioid-naive patients

is the prospectively randomized trial, in whichpatients are assigned to receive either thenewly introduced opioid or an alternative opi-oid agent. The research model for predictinghow patients will fare when they are switchedfrom their current opioid to a new one is thesubstitution study. In this model, patients al-ready receiving an opioid, after titrating to maxi-mum therapeutic benefit, are switched to the newopioid medication. We present here a substitu-tion study designed to predict the benefits andadverse effects that patients may experience whenthey substitute morphine sulphate in combina-tion with dextromethorphan (MorphiDex

®

,MS:DM) for their current opioid regimen.

More specifically, the objective of this open-label study was to determine the appropriateconversion regimens from other oral or trans-

Address reprint requests to:

Eric Chevlen, MD, St. Eliza-beth Hospital, 1044 Belmont Avenue, Youngstown,OH 44501, USA.

Accepted for publication: September 17, 1999.

Vol. 19 No. 1(Suppl.) January 2000 Conversion from Opioid Analgesics S43

dermal opioid analgesic medications to MS:DMin patients with moderate to severe chronicpain of any etiology requiring daily use of anopioid analgesic. In addition to evaluating themorphine daily dose during MS:DM treatmentcompared to the prestudy opioid morphineequivalent dose, we assessed patient satisfactionwith analgesic medication and safety.

Study Design

This multicenter, open-label study in pa-tients with moderate to severe chronic painwho required daily use of opioid analgesicsconsisted of two parts: an initial 2-wk study pe-riod in which patients were converted to a satis-factory dose of MS:DM, and a long-term exten-sion study to evaluate safety.

The initial dose of MS:DM was approxi-mately half the morphine-equivalent dose ofthe prestudy opioid. Patients were instructedto rapidly titrate the dose of study drug for thetotal management of pain, including break-through pain, to achieve satisfactory analgesia.Patients were also instructed not to take morethan 360 mg/day of MS:DM without the ap-proval of the principal investigator.

Inclusion and Exclusion Criteria

Patients included in the study were

$

18years of age, had severe or moderate chronicpain requiring daily opioid therapy, had atleast some pain relief from their current opi-oid, had life expectancy

.

3 mo, gave writteninformed consent, and if female, were post-menopausal, infertile, or using effective con-traception.

Patients were excluded from the study if theywere pregnant or breast-feeding, had allergiesto or were hypersensitive to opioids or dex-tromethorphan, had used monoamine oxidaseinhibitors within 2 wk before study entry, wereusing other forms of dextromethorphan, or re-quired

.

600 mg morphine daily. However, thestudy design allowed this dose limit to be ex-ceeded, on an individual patient basis, withpermission from the sponsor.

Safety and Efficacy Evaluations

Safety was evaluated by asking patients aboutadverse events and by recording volunteered

or observed information. The investigatorscored adverse events as mild, moderate, or se-vere. In addition, vital signs were monitored,and repeated neurological examinations wereperformed.

The daily dose of MS:DM was determined bythe number of doses recorded daily in the pa-tient diaries and actual pill count performed atthe study sites. The total daily dose of studydrug was compared to that of the patient’s pre-study morphine-equivalent daily dose. Thenumber of daily doses of tablets/capsules thepatient required to achieve satisfactory paincontrol was compared for MS:DM and the pre-study opioid. A global assessment of prestudyopioid was obtained at baseline by asking pa-tients how they rated their prestudy medica-tion. This same question was asked at eachstudy visit during MS:DM treatment. The rat-ing scale was as follows: poor, fair, good, verygood, and excellent.

Results

Of 592 patients screened, 578 took

$

1 doseof MS:DM and were evaluated for safety. Four-teen patients were excluded from the safetyanalysis because they never took a dose or tooka dose but were not available for further assess-ment. The efficacy population consisted of 457patients who did not violate the inclusion orexclusion criteria and who took the study drugfor

$

10 days.Study demographics for this general chronic

pain population are summarized in Table 1.Most patients had nonmalignant pain of

various etiologies (93%), and a minority had

Table 1

Patient Demographics (ITT Population)

Age (yr)Mean 578 50.8Range 23–86

Sex (

n

, %)Male 253 (44%)Female 325 (56%)

Race (

n

, %)White 533 (93%)African-American 31 (8%)

Prestudy Opioids (

n

)Hydrocodone 162Oxycodone 142Multiple opioids 141

S44 Chevlen Vol. 19 No. 1(Suppl.) January 2000

cancer pain (7%). Investigators rated the pa-tients’ pain as predominantly neurologic orsomatic. Among the total population, neuro-logic pain (60%) was more frequently reportedthan somatic pain (40%) and many patientshad more than one type of pain. Somatic painwas the predominant pain type among patientswith cancer. Neurologic pain was the predomi-nant type among patients without cancer.

Average Daily Dose of MS:DM

During week 2, the mean daily morphinedose in MS:DM for all patients (

N

5

457) was104.4 mg, a significantly lower dose than theprestudy morphine equivalent dose (132.7 mg,

P

5

0.0001). Patients were instructed to starttaking half of their baseline morphine equiva-lent dose as MS:DM and to rapidly titrate theirdose up or down during the study period. Thedose decreased sharply in the first week, thenincreased slightly during week 2, as the pa-tients titrated to satisfactory pain control.

Data were also analyzed for patients taking1–120 mg/day,

.

120–240 mg/day,

.

240–360mg/day, or

.

360 mg/day. In the three lowerdose range groups (which included all but sixpatients), the average daily dose of morphinedecreased from the prestudy morphine equiva-lent daily dose during the 2-wk study period(Fig. 1).

Analyses by type of pain (musculoskeletal,neuropathic, cancer, or other pain) indicatethat these pain syndromes were treated with anaverage of 100–150 mg/day (morphine) dur-ing MS:DM therapy. Patients with musculoskel-

Fig. 1. Mean daily dose of MS:DM by overall daily dose range and visit. Study patients were divided into four dos-age groups according to the average daily dose of MS:DM they were taking at the end of the 2-wk study period. Theaverage daily dose of morphine (or equivalent) that patients were taking at prestudy (open bars), during week 1(shaded bars), and during week 2 (solid bars) are shown. Except for the group of six patients who were takingdoses .360 mg/day at the end of week 2, the mean daily amount of morphine decreased for patients on Morphi-Dex® compared to their prestudy opioid.

Table 2

Mean Daily Dose of MS (Taken as MS:DM) by Pain Indication

Week 2

Pain Indicaiton

n

Mean (mg)

Musculoskeletal 271 152.2Neuropathic 60 128.0Cancer 24 110.6Other 19 101.1


etal pain (72% of patients) had the highestmean MS daily dose (152.2 mg/day). Themean daily dose for patients with neuropathic,cancer, and other pain was 128, 110.6, and101.1 mg/day MS, respectively (Table 2).

Average Daily Dose of MS:DM During the Study Extension Phase

The mean daily dose for the 374 patients whocontinued in the study extension was 143 mg at

the end of week 2 (day 14) of the conversionphase. During the 10-month study extension,the mean daily dose remained stable each month(range: 125.4–141.6 mg/day) (Table 3, Fig. 2).

Data were analyzed for three prestudy mor-phine equivalent dose ranges:

#

99 mg/day,100–199 mg/day, and

$

200 mg/day. Themean daily dose by dose range (determined atthe end of week 2) over the 10-mo extensionphase is shown in Table 3. The majority of pa-tients were in the lowest dose range group. Forthis group, the mean daily MS:DM (morphine)

Table 3

Mean Daily Dose of MS (Taken as MS:DM)

Study Month

Baseline (Week 2) 1 2 4 6 8 10

MS dose range mean (mg)

All subjects (

n

) (374) (374) (321) (269) (217) (183) (116)Mean (

6

SE) 143.0 (6.6) 125.4 (4.9) 130.7 (5.4) 135.9 (5.6) 141.6 (6.8) 137.4 (7.4) 136.3 (9.4)0–99 mg (

n

) (189) (189) (167) (142) (116) (106) (65)Mean (

6

SE) 61.0 (1.5) 63.1 (2.0) 68.9 (2.7) 76.4 (3.5) 78.2 (4.5) 79.3 (5.3) 75.7 (6.2)100–199 mg (

n

) (103) (103) (90) (74) (59) (45) (25)Mean (

6

SE) 142.1 (2.6) 131.6 (4.8) 147.9 (6.0) 168.7 (7.3) 180.4 (10.7) 176.5 (10.6) 149.1 (10.4)

.

200 mg (

n

) (82) (82) (64) (53) (42) (32) (26)Mean (

6

SE) 333.1 (16.3) 261.2 (10.6) 267.5 (12.4) 249.9 (12.2) 262.4 (13.7) 274.7 (15.6) 275.4 (17.5)

Fig. 2. The mean MS dose during the study extension phase. The mean 6 SE daily dose of MS (shaded bars) com-pared to the baseline morphine equivalent dose (white bars) by month. These data show essentially no increase indose over the 10-month extension phase.


dose increased slightly over the first 5 months,then stabilized over the next 5 months. In the100–199 mg/day dose group, the dose in-creased over the first few months and then de-

creased, approaching the baseline dose. In the

.

200 mg/day group, the mean daily dose wasconsiderably lower than the baseline dose dur-ing each month of the extension phase.

Fig. 3. Frequency of MS:DM dosing during week 2. The number and percent of patients who took 1, 2, 3, 4, 5, or.5 doses of MS:DM per day are displayed. The majority of patients (59%) took three or four doses of MS:DMper day.

Fig. 4. Overall assessments of prestudy opioid and MS:DM. Patients were asked to assess their prestudy opioidtreatment at baseline (white bars) and their MS:DM treatment at the end of week 2 (gray bars) as poor, fair, good,very good, or excellent. Significantly more patients rated MS:DM favorably (very good or excellent) compared totheir prestudy opioid (P 5 0.0001). Ratings for three subjects were missing.


Frequency of Dosing for MS:DM Compared with Prestudy Opioid

The majority of patients took three (32%) orfour (27%) doses of MS:DM per day (Fig. 3)for the total management of their pain, includ-ing doses of MS:DM required for break-through pain. No other medication was usedfor breakthrough pain. Since patients received15-, 30-, or 60-mg capsules, they could takemore than one capsule as a dose. Approxi-mately 50% of patients took three or fewerdoses per day and approximately 77% tookfour or fewer doses per day.

Patients who entered the study taking mor-phine were taking an average of 7 tablets perday, 3.3 tablets of extended-release morphine,and 3.7 tablets of immediate-release morphinefor breakthrough pain. The number of tablets

per day was similar for those patients who tookoxycodone prestudy.

Overall Assessment of Prestudy Opioid and MS:DM

Patients were requested to give an assess-ment of their prestudy opioid therapy at base-line and their MS:DM therapy at the end ofweeks 2, 6, and 10. They were asked how theyrated the drug (poor, fair, good, very good, orexcellent). Overall, at the end of week 2, 47%of the patients rated MS:DM therapy favorably(very good or excellent). At baseline, 14% gavefavorable ratings for their prestudy opioid ther-apy (Fig. 4). This difference, indicating patientpreference for MS:DM, was statistically signifi-cant (

P

5

0.0001). Patients continued to give

Fig. 5. Favorable ratings of prestudy opioid and MS:DM. The percent of patients who rated their opioid treatmentfavorably (very good or excellent) is displayed. At week 2, favorable ratings for MS:DM were significantly higherthan for the prestudy opioids (P 5 0.0001), and remained significantly high at weeks 6 and 10 of the study exten-sion (*indicates P 5 0.0001). Rating for one subject at baseline unknown.

Table 4

Ratings of Pain Medication by Pain Indication

Number (%) of Patients with Favorable Ratings (Excellent/Very Good)

Week 0 Week 2 Week 6 Week 10

Pain Indication

n

(%)

n

(%)

n

(%)

n

(%)

Musculoskeletal 33 (12.2) 133 (49.1) 148 (55.2) 134 (58.8)Neuropathic 11 (18.3) 30 (50.0) 38 (63.3) 31 (62.0)Cancer 6 (25.0) 16 (66.7) 11 (52.4) 10 (71.4)Other 2 (10.5) 15 (78.9) 16 (84.2) 12 (70.6)


higher ratings to MS:DM during the study ex-tension period, with 58% and 61% rating thedrug as very good or excellent at week 6 andweek 10, respectively (Fig. 5).

Other Analyses

Patient responses were also analyzed by painindication, MS:DM dose range (morphine-equivalent range 1–99, 100–199,

.

200 mg/day) and strength of prestudy opioid:

Response by Pain Indication

Of the patients with musculoskeletal pain,49% rated MS:DM very good or excellent, com-pared to only 12% for their prestudy opioid.During the study extension period, the prefer-

ence for MS:DM continued; 55% of patientsrated the drug favorably at week 6 and 59% atweek 10 (Table 4). Similar results were seen forpatients with neuropathic, cancer or otherpain. In each group, the percentage of patientswith favorable ratings for MS:DM was higherthan for the prestudy opioids and remainedhigh throughout the 10-wk study extension.

Response by Dose Range

Ratings for MS:DM were similar regardlessof the daily dose of MS:DM patients were tak-ing. Data were analyzed by mean daily doseranges: 0–99 mg/day, 100–199 mg/day, or

.

200mg/day. Slightly more than 50% of the pa-tients in each group rated MS:DM as very goodor excellent at the end of week 2 (Table 5).

Table 5

Global Ratings of Pain Medication by Dose Range

Number (%) of Patients with Favorable Ratings (Excellent/Very Good)

Week 0 Week 2 Week 6 Week 10

Dose Range

n

(%)

n

(%)

n

(%)

n

(%)

0–99 mg 20 (10.7) 99 (52.4) 101 (54.9) 94 (59.8)100–199 mg 17 (16.5) 53 (51.5) 59 (57.9) 51 (58.6)

$

200 mg 15 (18.3) 42 (51.2) 53 (64.7) 42 (64.6)

Fig. 6. Ratings of prestudy opioid and MS:DM. The percent of patients who rated their opioid treatment favorablyat prestudy (white bars) and week 2 (shaded bars) is displayed by type of prestudy opioid; strong, oxycodone, hy-drocodone, and weak opioids. Strong opioids include morphine, fentanyl, hydromorphone, etc. Weak opioids in-clude Darvon®, Darvocet®, Tylenol® with Codeine, etc. A significantly greater percentage of patients gave favorableratings for MS:DM compared to strong opioids, oxycodone, hydrocodone, or weak opioids (P , 0.01).


The percentage continued to increase at weeks6 and 10 in the study extension.

Response by Opioid Strength

Of the patients taking strong opioids (mor-phine, fentanyl, hydromorphone, etc.) at studystart, approximately 22% rated their opioidtherapy as very good or excellent at baseline,whereas 47% rated MS:DM as very good or ex-cellent at the end of week 2 (

P

5

0.0047) (Fig.6). Similarly, approximately 14% of patientstaking oxycodone (IR oxycodone, OxyContin

®

,Percocet

®

, Percodan

®

, etc.) prestudy ratedtheir therapy very good or excellent, comparedto 45% for MS:DM (

P

5

0.0001). Of patientstaking hydrocodone (Vicodin

®

, Lorcet

®

, gener-ics), 10% rated their prestudy drug favorablyand 48% rated MS:DM favorably (

P

5

0.0001).For patients taking weak opioids (Darvon

®

,Darvocet

®

, Tylenol

®

with Codeine, etc), thepercentage with favorable ratings was 9% forthe prestudy opioid, compared to 36% forMS:DM (

P

5

0.0073).

Safety

Safety assessments showed no difference invital signs during the study. Similarly, repeated

neurological examinations showed no clini-cally significant changes during treatment withMS:DM. The most common adverse events re-ported during the study were those frequentlyreported by patients taking opioids: somnolence(24%), nausea (23%), constipation (17%), diz-ziness (17%), and headache (12%) (percent-age of patients reporting the AE at least once).The majority of adverse events were consid-ered mild to moderate in severity.

Conclusions

The mean daily dose of MS:DM was signifi-cantly lower than the morphine equivalentdose of prestudy opioid. Patient satisfactionratings of the medication were significantlyhigher for MS:DM than for prestudy opioids.Results from the study extension indicate thatpatients’ daily doses were stable over a 10-moperiod, suggesting that the dextromethor-phan component, in addition to potentiatingmorphine analgesia, may also inhibit the devel-opment of tolerance to the opioid. MS:DM hada safety profile similar to that of prestudy opio-ids, and appears safe and effective in the treat-ment of moderate to severe chronic pain.

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Morphine with Dextromethorphan: Conversion from Other Opioid Analgesics