Drug Review

Brand Name:  DepoDur^Ô

Generic Name:  Morphine sulfate extended-release liposome injection

Manufacturer:  Endo Pharmaceuticals, Inc.

Drug Class:  Epidural opioid analgesics

Uses: ^1,2,3 

Labeled Uses:  

·        Single-dose, epidural administration, at the lumbar level, for the treatment of pain following major surgery.  DepoDur^Ô is not intended for intravenous, intrathecal, or intramuscular injection. 

Mechanism of Action: ^1,2 DepoDur^Ô, the first of its kind, is a liposome-encapsulated formulation of morphine sulfate suspension.  The morphine is slowly released from the multivesicular liposomes after injection into the epidural space.  Morphine is a pure opioid agonist and results in analgesia through its interaction at opioid receptors, most specifically the m-receptor. 

Pharmacokinetics: ^1,2  After the active drug is released from the liposomes and is absorbed systemically, the distribution, metabolism, and excretion for DepoDur^Ô are similar to all other morphine formulations.  No pharmacokinetic studies have been conducted in pediatric patients. 

Table 1:  Morphine Plasma Pharmacokinetic Parameters (Mean + SD) Following Epidural

                Administration of DepoDur^{Ô 1,2}

UK=unknown

* In studies, patients who were > 65 years of age, had hepatic failure, or renal impairment, all had

   decreased clearances.

Metabolism: DepoDur^Ô, like other morphine formulations, is metabolized primarily in the liver

through glucuronide conjugation.  With the exception of the small portion (less than 5%) that is demethylated, virtually all morphine is converted to glucuronide metabolites including morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).  Only M6G has been shown to possess analgesic activity. 

Excretion:  Approximately 10% of DepoDur^Ô is excreted in the urine as parent drug.  Most of the

drug is excreted as M3G and M6G metabolites.  Only 7-10% is excreted in the feces and a small amount of the metabolites are excreted in the bile with some enterohepatic cycling. 

Efficacy:  No efficacy studies have been formally published to date.  The following studies were presented as posters at the 23^rd Annual Scientific Meeting of the American Pain Society on May 6-9, 2004 in Vancouver, BC. 

Viscusi E, Martin G, Hartrick C, Singla N, Manvelian G.  Encapsulated epidural morphine provides up to 48 hours of postoperative pain relief after total hip arthroplasty [abstract].  23^rd Annual Scientific Meeting of the American Pain Society; May 6-9, 2004; Vancouver, BC.  Poster #880.

http://ampainsoc.org/abstract/2004/data/880/index.html.  [Accessed 13 Dec 2004].

This study was an experimental, placebo-controlled study involving 194 patients undergoing total hip arthroplasty.  The study does not mention if and/or how patients were randomized.  Prior to surgery, each patient was given either an epidural injection of placebo or DepoMorphine (now referred to as DepoDur^Ô) 15, 20, or 25 mg.  Intravenous fentanyl via PCA pump was given for breakthrough pain postoperatively.  The primary assessment measure in the study was total postoperative fentanyl consumption during the first 48 hours following surgery.  Secondary assessment measures were pain intensity both at rest and during activity, pain control, and safety.  Primary assessment showed that mean (+ SD) fentanyl consumption was significantly lower for patients using all three strengths of DepoMorphine combined versus placebo, 510 + 708 mg vs. 2091 + 1803 mg, respectively (P < 0.0001).  In the active treatment group, 46% of patients did not use any fentanyl throughout the first 24 hours and 25% used none throughout the full 48 hours compared to 2% percent of patients in the placebo group that used some fentanyl within the first 24 hours and 2% that used fentanyl within the full 48 hours (P < 0.01).  Secondary measures also produced statistically significantly results in favor of the DepoMorphine group.

There were many limitations in this study including: lack of randomization and blinding, failure to include the number of patients in each group, lack of patient baseline characteristics, and failure to mention whether patients received concomitant medications.  Due to the degree of limitations within the study, it cannot be concluded with any certainty that DepoMorphine was at all superior to placebo in the treatment of postoperative pain from total hip arthroplasty.⁵

Carvalho B, Riley E, Manvelian G.  Improved postoperative pain control following elective C-section with a single-dose, encapsulated, epidural morphine [abstract].  23^rd Annual Scientific Meeting of the American Pain Society; May 6-9, 2004; Vancouver, BC.  Poster #877.

http://www.ampainsoc.org/abstract/2004/data/877/index.html.  [Accessed 13 Dec 2004].

In this multicenter, experimental, randomized study, 75 women undergoing elective cesarean section received either an encapsulated epidural morphine injection (DepoMorphine) of 5, 10, or 15 mg or a standard 5 mg morphine sulfate injection after cord clamping.  Prior to this, study participants in both groups received a 12 to 15 mg intrathecal bupivacaine injection with 10-mg fentanyl.  The primary assessment measure in this study was total supplemental opioid use within the first 48 hours following the surgery.  Secondary assessment measures were pain intensity both during rest and activity (measured on a visual analog scale), and pain control throughout the following 48 hours post-surgery.  Results for the primary assessment measure showed that mean (+ SD) total supplemental opioid medication used within 48 hours was lower for patients using all three strengths of DepoMorphine combined, 30 + 27 mg, versus placebo, 47 + 34 mg, (P < 0.05).  On the second postoperative day, mean use of supplemental opioids was also lower for DepoMorphine, 12 + 9 mg in the 10 mg depot group, 11 + 21 mg in the 15 mg depot group, and 20 mg in the standard 5 mg morphine sulfate group (P < 0.05).  All secondary assessment measures were also statistically significant in favor of DepoMorphine in all strengths versus placebo.  Limitations of this study include: no blinding, no mention of the number of patients included in each treatment group, no patient baseline characteristics were given, no mention of the day two supplemental opioid dose in the 5 mg depot group, and no information was provided on other concomitant medications that patients may have been taking.  Because this study also has major limitations, more information is needed to conclude whether DepoMorphine is in fact a superior therapy to standard morphine sulfate injection for pain following C-section.⁶ 

Hartrick C, Martin G, Kantor G, Manvelian G.  Evaluation of a novel encapsulated, epidural morphine for pain control after elective knee arthroplasty [abstract].  23^rd Annual Scientific Meeting of the American Pain Society; May 6-9, 2004; Vancouver BC.  Poster #879.  http://ampainsoc.org/abstract/2004/data/879/index.html.  [Accessed 13 Dec 2004].

A randomized, double-blind, experimental study was conducted to assess the efficacy of single-dose DepoMorphine versus IV PCA morphine following knee arthroplasty in 168 patients.  Prior to surgery, 51 patients received a 20-mg injection of DepoMorphine, 61 patients received 30 mg, and 56 received a sham epidural (IV PCA morphine group).  Initially, patients in the depot group received IV hydromorphone and then once the analgesia was adequate, they were able to use a placebo PCA pump.  If the pain was not alleviated with the initial IV hydromorphone, then patients received increase placebo PCA and an additional IV hydromorphone bolus injection.  Initially, patients in the IV PCA morphine group received IV morphine until analgesia was adequate and thereafter, they were able to use an IV PCA morphine pump.  If the pain was not alleviated with the initial IV PCA morphine, then patients received increased IV PCA morphine and bolus IV placebo injection.  Primary assessment measures were recalled pain intensity, postoperative opioid usage, time to first postoperative opioid use, and safety.  All primary assessment measures were found to be statistically significant in favor of DepoMorphine.  First, recalled pain intensity scores were lower in those assigned to the DepoMorphine 30 mg group (32 + 19) than in those assigned to the IV PCA morphine group (39 + 19), (P < 0.05).  Second, overall opioid use was 39 + 42 mg in the 30 mg depot group, 44 + 34 mg in the 20 mg depot group, and 132 + 65 mg in the IV PCA morphine group, P < 0.0001).  All IV PCA morphine patients required supplemental opioids; however, only 72% and 85% of patients in the 30 mg depot group and 86% and 92% of patients in the 20 mg depot group required supplemental opioids at 24 and 48 hours post-op, respectively (P < 0.05).  Finally, median time to first postoperative opioid use was significantly longer with DepoMorphine and with the exception of an increase incidence of pruritis in the depot group (57% vs. 16% in the IV PCA morphine group; P < 0.01), adverse event occurrences were similar across groups.  Limitations of this study include: convoluted study design which may have led to unblinding, failure to include patient baseline characteristics, failure to include participant recruitment methods, failure to quantify how much time it took in both groups to first postoperative opioid use, and failure to mention any concomitant medications that patients may have taken.  One may conclude from this study that DepoMorphine is an additional option for the treatment of postoperative pain in knee arthroplasty, but it does not confirm that DepoMorphine is superior to IV PCA morphine.  Future studies with a better study design are needed.⁷

Adverse Effects: ^1,2

The most common adverse reactions occurring in > 10% of patients treated with DepoDur^Ô include:

• decreased oxygen saturation                    ·   hypotension                  ·   urinary retention                         

• vomiting                                              ·   constipation                 ·   nausea                            

• pruritis                                                  ·   pyrexia                         ·   anemia                         
• headache                                             ·   dizziness

Adverse events occurring in 5-10% of study patients include:

• hypoxia                                                ·   tachycardia                              ·   insomnia
• flatulence

Less common adverse events occurring in 2-5% of study patients include:

• respiratory depression                                ·   hypercapnia                  ·   paralytic ileus
• somnolence                                         ·   bladder spasm               ·   abdominal distension
• hypoesthesia                                         ·   hypertension                ·   oliguria
• bradycardia                                         ·  anxiety                          ·   back pain
• increased sweating                                  ·   dyspepsia                                ·   rigors
• dyspnea                                              ·   hypokalemia                 ·   paresthesia
• decreased hematocrit

Drug Interactions: ^1,2

• Local Anesthetics- epidural 3-mL lidocaine 1.5% and epinephrine 1:200,000 test dose.  In studies, when DepoDur^Ô was administered immediately following a test dose, the T_max concentration of morphine was slightly delayed and the C_max was approximately doubled.  When administered after 15 minutes, there was virtually no difference when compared to the no test dose control group.   
• CNS Depressants.  The CNS depressant effects of morphine are additive and can result in an increased risk of respiratory depression, hypotension, deep sedation, or even coma when used in conjunction with the following agents:

Ø     Alcohol, other opiates, sedatives, hypnotics, general anesthetics, droperidol, and phenothiazines, or other tranquilizers.

• Neuromuscular blocking agents.  When morphine is added concomitantly with neuromuscular blocking agents, morphine associated respiratory depression may delay the recovery of spontaneous pulmonary ventilation.
• Monoamine oxidase inhibitors.  MAOIs may potentiate the effects of morphine. DepoDur^Ô should not be coadministered with MAOIs or taken within 14 days of finishing an MAOI.

Warnings and Precautions: ^1,2,3

• All patients must be monitored for respiratory depression and other serious adverse effects in a fully equipped and staffed environment for at least 48 hours following administration.  The facility must be equipped to resuscitate patients in the event of morphine overdosage which includes the use of narcotic antagonists such as naloxone when necessary.  The results of clinical trials with DepoDur^Ô showed that 90% of respiratory depression occurred within 24 hours of administration; however, in 0.6% of patients, onset occurred after 48 hours. 
• DepoDur^Ô should only be administered by epidural at the lumbar levels only. 
• Extreme caution should be used when administering DepoDur^Ô to elderly, debilitated, hypoxic, or hypercapnic patients.
• DepoDur^Ô should never be mixed with or coadministered with any other local anesthetics.
• Once DepoDur^Ô is administered; no other medication should be administered into the epidural space for a minimum of 48 hours.
• Do not use an in-line filter during the administration of DepoDur^Ô.
• DepoDur^Ô should not be given to women for vaginal labor and delivery.
• As with other formulations of morphine, liposomal extended-release morphine may be associated with seizures, hypotension or syncope, biliary colic, and urinary retention.  Caution should be used in those with a history of seizures, reduced circulating blood volume, impaired myocardial function, biliary tract disease, and disturbances of micturition, i.e. prostatic hypertrophy. 

Contraindications: ^1,2,3

·        Hypersensitivity to active ingredients or any component of the drug.

·        Respiratory depression.

·        Acute or severe bronchial asthma.

·        Upper airway obstruction.

·        Paralytic ileus.

·        Circulatory shock.

·        Known or suspected head injury or increased intracranial pressure.

·        Conditions that preclude epidural administration.

Pregnancy and Lactation: ^1,2 DepoDur^Ô is classified as pregnancy category C.  Morphine also crosses the placenta and has been found in breast milk.  Women who are pregnant or nursing should not take morphine sulfate unless the benefit clearly outweighs the risks to the fetus. 

Dosing/Administration: ^1,2,3

Usual Dose:

• DepoDur^Ô is a sterile, preservative free morphine sulfate suspension contained within liposomes suspended in 0.9% sodium chloride solution.  It is available in 10 mg/mL single-use vials in 1, 1.5, and 2 mL volumes.  
• DepoDur^Ô may be administered by epidural needle or catheter at the lumbar level only.  In-line filters should not be used. 
• DepoDur^Ô should be administered prior to surgery or after the clamping of the umbilical cord during cesarean section.  
• Although each patient should be evaluated individually for optimum dosing, the following are the  recommended dosing guidelines according to type of surgery:

Ø     Major orthopedic surgery of the lower extremity:  15 mg

Ø     Lower abdominal surgery:  10 mg – 15 mg

Ø     Pelvic surgery:  10 mg – 15 mg

Ø     Cesarean section:  10 mg

Geriatric Dose:  

• The recommended dose for elderly patients (> 65 years) or debilitated patients follow the usual dosing guidelines according to surgery type; however, doses should be given at the low end of the range.
• Caution should be exercised when determining if DepoDur^Ô therapy would be appropriate in this population.  Because they are at greater risk for respiratory depression and other adverse drug reactions, vigilant perioperative monitoring should be employed. 

Pediatric Dose:

• The safety and effectiveness of DepoDur^Ô has not been evaluated in patients 18 years of age or less and is therefore, not recommended.

Renal and/or Hepatic Impairment:

• Systemic morphine pharmacokinetics are altered in patients with cirrhosis or renal impairment; however, since DepoDur^Ô is indicated for single-dose administration, morphine or its metabolites should not accumulate.  The literature does not specify whether a dose adjustment is necessary.

Storage: ^1,2 DepoDur^Ô should be stored in the refrigerator between 2° to 8°C (36° to 46°F) until ready to use.  An unopened vial may be kept at 15° to 30° C (59° to 86° F) for a period of up to 7 days; however, once the vial is opened and DepoDur^Ô is withdrawn, it may only be held at this temperature for up to 4 hours before administration.  Do not allow DepoDur^Ô to freeze.  If it is suspected to have frozen, do not administer.    

Conclusion:  When making a clinical decision as to whether DepoDur^Ô should be considered as a treatment option for the patient undergoing major surgery, overall safety, efficacy, cost, and convenience for the patient must be considered.  Several clinical trials performed with DepoMorphine (renamed as DepoDur^Ô) have shown it to be as effective as or more effective than standard morphine therapy, IV PCA morphine, and placebo.  However, the validity and credibility of these studies are weak since they are riddled with limitations. The manufacturers of DepoDur^Ô maintain that it would offer a full 48 hours of pain control without the need for external tubes and pumps that are often required with other forms of postoperative pain management. DepoDur^Ô differs from most epidural morphine formulations in that it does not require an indwelling catheter for continuous pain relief.  Because such catheters can be uncomfortable to the patient and limit their mobility, DepoDur^Ô would eliminate this hindrance.  Additionally, DepoDur^Ô would significantly decrease the likelihood of infection that comes as a result of indwelling catheters while also allowing for the administration of anticoagulant therapy.⁴ DepoDur^Ô does have valuable advantages and may be a first line treatment option in the future once several well-designed studies are able to demonstrate its true efficacy.  Until then, DepoDur^Ô may be used in practice but only when other established treatment options are unavailable or unreasonable.

References:

 1. DepoDur^Ô [package insert].  Endo Pharmaceuticals, Inc.; Chadds Ford, PA; May 2004.

2.  Facts and Comparisons Formulary Review:  morphine sulfate extended-release liposome injection.

     www.formularymonographs.com  [Accessed November 2004].

3.  Patient Information: DepoDur^Ô (morphine sulfate extended-release liposome injection).

     Endo Pharmaceuticals, Inc.; Chadds Ford, PA; May 2004.

4.      Press Release:  Two days of post-surgical pain relief now possible with just one shot.  Endo

Pharmaceuticals, Inc.; Chadds Ford, PA; Dec 6 2004.

 5.  Viscusi E, Martin G, Hartrick C, Singla N, Manvelian G.  Encapsulated epidural morphine provides up

     to 48 hours of postoperative pain relief after total hip arthroplasty [abstract].  23^rd Annual Scientific

     Meeting of the American Pain Society; May 6-9, 2004; Vancouver, BC.  Poster #880.

     http://ampainsoc.org/abstract/2004/data/880/index.html.  [Accessed 13 Dec 2004].

6.  Carvalho B, Riley E, Manvelian G.  Improved postoperative pain control following elective C-section

     with a single-dose, encapsulated, epidural morphine [abstract].  23^rd Annual Scientific Meeting of the

     American Pain Society; May 6-9, 2004; Vancouver, BC.  Poster #877.

     http://www.ampainsoc.org/abstract/2004/data/877/index.html.  [Accessed 13 Dec 2004].

7.  Hartrick C, Martin G, Kantor G, Manvelian G.  Evaluation of a novel encapsulated, epidural morphine

     for pain control after elective knee arthroplasty [abstract].  23^rd Annual Scientific Meeting of the

     American Pain Society; May 6-9, 2004; Vancouver BC.  Poster #879. 

     http://ampainsoc.org/abstract/2004/data/879/index.html.  [Accessed 13 Dec 2004].

    Karen Baird, PharmD Candidate.