Morphine sulfate is available in a variety of concentrations (e.g., ranging from 0.5 to 50 mg/mL), packages (e.g., vials, ampuls, cartridges, syringes, patient-controlled analgesia [PCA] vials, auto-injectors), and sizes.3484; 3485; 3486; 3487; 3488; 3489; 3490; 3491 Some formulations are preservative free and may be labeled for epidural and intrathecal administration.3484; 3485; 3486 Other morphine products may contain various preservatives, antioxidants, and buffers, including edetate disodium, sodium metabisulfite, benzyl alcohol, and citric acid;3487; 3488; 3489; 3490; 3491 specific product labeling should be consulted for additional formulation details and labeled routes of administration of each product.
Morphine also is available in some countries as the hydrochloride and tartrate salts.
pH
The pH of many morphine sulfate products falls within the range of 2.5 to 6.5,3484; 3487; 3489; 3491 with some products exhibiting a more narrow pH range of 2.5 to 43488 or a pH of 4.5;3485; 3486 specific product labeling should be consulted for the pH of a specific product.
Morphine sulfate (David Bull) 7.5 mg/mL in sodium chloride 0.9% had a pH of 3.5.2161
Osmolality
Morphine sulfate (David Bull) 7.5 mg/mL in sodium chloride 0.9% had an osmolality of 236 mOsm/kg.2161
Trade Name(s)
Astramorph PF, Duramorph, Infumorph, Mitigo
Morphine sulfate may be administered by slow, direct intravenous injection3488; 3490 or by intramuscular3489; 3490 or subcutaneous injection; the drug also may be given by slow intravenous injection or continuous intravenous infusion after dilution.3491 For continuous intravenous infusion using an infusion pump, one manufacturer recommends a final morphine sulfate concentration of 0.2 to 1 mg/mL in dextrose 5%;3491 more concentrated solutions also have been used. Some products containing no preservatives may be labeled for intrathecal or epidural administration.3484; 3485; 3486
Some higher-concentration morphine sulfate products (e.g., 10, 25, or 50 mg/mL) are not recommended for subcutaneous, intramuscular, intravenous, or neuraxial injection of individual doses; such products may be labeled for intraspinal administration (with or without dilution) using a continuous microinfusion device3485; 3486 or for continuous intravenous infusion only after dilution using an infusion pump.3491
Intact containers should be stored in the carton at controlled room temperature and protected from freezing and light.3484; 3485; 3486; 3487; 3488; 3489; 3490; 3491 Manufacturers state that the products should not be heat sterilized3484; 3485; 3486; 3487; 3488; 3491 or autoclaved.3490 Morphine sulfate darkens with age and upon prolonged exposure to light;3488; 3490; 3491 the injection should not be used if it is darker than pale yellow in color or if is discolored in any other way.3484; 3485; 3486; 3487; 3490; 3491
Undiluted morphine sulfate 10 mg/mL, stored in 100-mL glass vials and polyvinyl chloride (PVC) bags, exhibited no loss in 30 days at 23°C.1394
Morphine sulfate (Wyeth) 1 mg/mL in bacteriostatic sodium chloride 0.9% containing benzyl alcohol 0.9%, when stored in glass vials with protection from light, exhibited no loss at 4°C and a 4% loss at 22°C after 91 days.1583
Morphine sulfate 15 mg/mL and 2 mg/mL diluted with sterile water for injection stored at 4 and 24°C in 200-mL PVC bags (Baxter) was stable at both temperatures with little loss in 15 days.1504
Morphine sulfate under simulated summer conditions in paramedic vehicles was exposed to 26 to 38°C over 4 weeks. No drug loss occurred under these conditions.2562
Morphine sulfate 1 mg/mL compounded in sodium chloride 0.9% was packaged in 100-mL polypropylene infusion bags and was autoclaved at 121°C for 20 minutes for sterilization. No visible precipitation appeared and microparticulate levels remained acceptable in all samples when stored at 25°C for 3 years and at 30 and 40°C for 6 months. No evidence of evaporation was found in the samples, and no loss of morphine sulfate occurred in any of the solutions throughout the study. While PVC bags cannot be autoclaved and exhibit excessive loss of water through evaporation upon storage, polypropylene bags can be successfully used for compounding bags of morphine sulfate solutions with 3-year stability for use in patient-controlled analgesia.2665
pH Effects
Morphine sulfate is relatively stable at acidic pH, especially below pH 4, but degradation increases greatly at neutral or basic pH. Degradation is often accompanied by a yellow to brown discoloration in the normally colorless solution.1072; 2170
Morphine sulfate stability at a low concentration of 2 mg/mL in an admixture with ketamine hydrochloride in sodium chloride 0.9% with the pH adjusted over a range of pH 5.5 to 7.5 was stored at room temperature over 4 days. No difference in physical or chemical drug stability was observed among the samples.2786
However, at higher concentrations of morphine at pH values of 6.4 and above, precipitation may occur. Morphine sulfate at about 18 mg/mL mixed with ketamine hydrochloride exhibited a pH near 4.85. Adjusting the pH higher with sodium bicarbonate injection up to pH 5.9 resulted in mixtures that were clear over 24 hours at 21°C. However, adjusting to pH 6.2 resulted in precipitation within 2 hours. Adjusting to pH 6.4 and above resulted in immediate precipitation.2787
Freezing Solutions
Manufacturers state that morphine sulfate products should not be frozen.3484; 3485; 3486; 3487; 3488; 3489; 3490; 3491
Morphine sulfate (Lilly) 1 and 2 mg/mL in dextrose 5% and sodium chloride 0.9% in PVC bags exhibited no loss during 14 weeks of frozen storage at -20°C.1286
Syringes
In 2015, reports of decreased potency of certain drugs (e.g., morphine sulfate) stored in Becton Dickinson syringes for extended periods (i.e., exceeding 24 hours) were confirmed by the manufacturer of these syringes; the cause of this change was later identified to be the inclusion of an alternate rubber stopper in the plunger of certain product lots of syringes.3029; 3036; 3037; 3039; 3041; 3042 Decreased potency was not observed when the syringes were filled and used promptly.3037 Use of the alternate stopper was later discontinued and use of the primary stopper in such syringes was resumed; however, Becton Dickinson states that its general-use syringes are cleared by FDA for immediate use in fluid aspiration and injection and that such syringes, regardless of the stopper material, have not been cleared by FDA for use as a closed-container system.3391
Prefilled into plastic syringes with syringe caps (Braun), morphine sulfate is stated to remain within acceptable limits of degradation for at least 69 days at room temperature.982
In another study, less than a 3% loss of morphine sulfate occurred in 12 weeks when stored in plastic syringes at 22°C and exposed to light. A smaller loss occurred when the morphine sulfate was stored at 3°C with light protection.1287
Morphine sulfate (Lilly) 1 and 5 mg/mL in dextrose 5% and sodium chloride 0.9% was packaged in 30-mL Plastipak (Becton Dickinson) syringes capped with Monoject (Sherwood) tip caps. Syringes were stored at 23°C in light and dark, 4°C protected from light, and frozen at -20°C protected from light for 12 weeks. Both concentrations at all 3 temperatures were stable for at least 6 weeks when protected from light. However, the samples stored at 23°C exposed to light were stable for 1 week, but developed unacceptable losses after that.1894
Morphine sulfate 2 mg/mL in sodium chloride 0.9% was packaged in 50-mL (Becton Dickinson) and 30-mL (Becton Dickinson and Sherwood) polypropylene syringes for use in patient-controlled analgesia and in stoppered glass vials. The samples were stored at room temperature in the dark for 6 weeks. Little loss of morphine sulfate occurred in the 50-mL syringes and the glass vials in 6 weeks. About 5% loss occurred when packaged in both Becton Dickinson and Sherwood 30-mL syringes. Addition of sodium metabisulfite 0.1% as an antioxidant increased the rate of drug loss up to 10% in 2 weeks.2040
Morphine sulfate 5 mg/mL in sodium chloride 0.9% and 50 mg/mL in sterile water for injection and also in sodium chloride 0.9% packaged as 20 mL in 30-mL polypropylene syringes were stored for 60 days at 4°C protected from light and 23°C exposed to normal fluorescent light. Other solutions were stored frozen at -20°C and at elevated temperature of 37°C for 2 days to simulate more extreme conditions during express shipping. Little or no morphine sulfate loss occurred in the 50-mg/mL samples stored for 60 days at 4 and 23°C even though slight yellow discoloration occurred after 30 days. The 5-mg/mL samples stored at 4 and 23°C exhibited about 4 to 5% loss in 60 days. The frozen and 37°C samples exhibited little or no change in morphine sulfate concentration in 2 days. However, samples of the 50-mg/mL concentration stored at -20 and 4°C and samples of the 5-mg/mL concentration stored frozen at -20°C precipitated upon low temperature storage. Although the precipitate redissolved upon warming at 37°C for several hours, large amounts of microparticulates in the tens of thousands per mL remained, possibly shed by the syringe components.2376
Morphine sulfate (Hospira) diluted to 1 mg/mL in dextrose 5% or sodium chloride 0.9% was packaged as 5 mL in 10-mL polypropylene syringes (Becton Dickinson) and stored at ambient room temperature protected from light.3887 The solutions remained clear and colorless with no loss of drug in 100 days.3887
Ambulatory Pumps
Walker et al. reported the stability of undiluted morphine sulfate (Sabex) 50 and 25 mg/mL, with and without sodium metabisulfite preservative, in portable infusion pump cassettes (Pharmacia) stored at 4 and 23°C.1505 At both concentrations with and without sodium metabisulfite at 4 and 23°C, samples remained clear and colorless.1505 Morphine sulfate losses of less than 10% were found during 31 days of storage.1505
Stiles et al. studied the stability of undiluted morphine sulfate 25 and 15 mg/mL in pump reservoirs (Pharmacia Deltec) stored at 5°C in the dark and 25°C for 30 days.1507 After the initial storage period, the solutions were subsequently stored at 37°C and pumped at a flow rate of 0.4 mL/hr for 3 days to simulate patient use.1507 No color change or precipitation occurred in any sample.1507 Little to no losses were detected; in fact, increased concentrations were observed, especially at room temperature.1507 The concentration increases were attributed to water evaporation during storage.1507 The authors recommended a maximum storage of 30 days under refrigeration and 14 days at room temperature because of the evaporation.1507
Elastomeric Reservoir Pumps
Morphine sulfate 15 mg/mL and 2 mg/mL diluted with sterile water for injection was stored at 4 and 24°C in Intermate 200 (Infusion Systems) and Infusor (Baxter) disposable elastomeric infusion devices.1504 In the Intermate 200 with 100 mL of morphine sulfate solution, little or no loss occurred in 15 days at either 4 or 24°C and even at 31°C (simulating use next to a patient’s skin or clothing).1504 In the Infusor, with 50 mL, losses of 5% or more were observed in 12 days in some containers.1504
Morphine sulfate 0.5 mg/mL in both dextrose 5% and sodium chloride 0.9% was evaluated for binding potential to natural rubber elastomeric reservoirs (Baxter). No binding was found after storage for 2 weeks at 35°C with gentle agitation.2014
Morphine sulfate 2 and 10 mg/mL is reported to be physically and chemically stable in Accufuser Plus silicone balloon infusers when stored at room temperature and refrigerated. Little or no loss of morphine sulfate occurred in 40 days.2678
Implantable Pumps
Morphine sulfate 10 mg/mL was filled into a VIP 30 implantable infusion pump (Fresenius) and associated capillary tubing and stored at 37°C. No morphine loss and no contamination from components of pump materials occurred during 8 weeks of storage.1903
Morphine sulfate (Infumorph) 20 mg/mL with clonidine hydrochloride (Boehringer Ingelheim) 50 mcg/mL and morphine sulfate 2 mg/mL with clonidine hydrochloride 1.84 mg/mL were evaluated in SynchroMed EL (Medtronic) implantable pumps with silicone elastomer intrathecal catheters at 37°C for 3 months. No visible incompatibilities were observed; delivered concentrations of both drugs were in the range of 94 to 99.6% throughout the study. Furthermore, no impairment of mechanical performance of the pump or any of its components was found.2477
An admixture of bupivacaine hydrochloride 25 mg/mL, clonidine hydrochloride 2 mg/mL, and morphine sulfate 50 mg/mL in sterile water for injection was reported to be physically and chemically stable for 90 days at 37°C in SynchroMed implantable pumps. Little or no loss of any of the drugs was found.2585
Clonidine hydrochloride and morphine sulfate powders were dissolved in ziconotide acetate (Elan) injection to yield concentrations of 2 and 35 mg/mL and 25 mcg/mL, respectively. Stored at 37°C, 11% ziconotide loss in 7 days, 4% clonidine loss in 20 days, and no morphine loss in 28 days occurred.2752
Other Devices
The stability of 2 intrathecal solutions of morphine sulfate 10 mg/mL in sodium chloride 0.9% (isobaric) and 5 mg/mL in dextrose 7% in water (hyperbaric) was evaluated. The solutions were stored at 4 and 37°C in glass ampuls and pump reservoirs composed of silicone rubber reinforced with polyester (Cordis Europa). No precipitation or discoloration and no loss of morphine sulfate or increase in degradation products occurred in the solutions in glass ampuls after 2 months at either temperature. However, in the pump reservoirs, the isobaric solution in sodium chloride 0.9% developed a yellow color. Furthermore, a decomposition product, pseudomorphine, was detectable in 3 days and increased to 1% in 1 month at 37°C. This level was 20 times that of the pseudomorphine found in the hyperbaric dextrose 7% in water solution under the same conditions. The decomposition was attributed to dissolved oxygen, ethylene oxide sterilant, and silicone rubber.1508
Central Venous Catheter
Morphine sulfate (Astra) 1 mg/mL in dextrose 5% was found to be compatible with the ARROWg+ard Blue Plus (Arrow International) chlorhexidine-bearing triple-lumen central catheter. Essentially complete delivery of the drug was found with little or no drug loss occurring. Furthermore, chlorhexidine delivered from the catheter remained at trace amounts with no substantial increase due to the delivery of the drug through the catheter.2335
Standardize 4 Safety
One or more standardized concentrations for this drug have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. (See Standardize 4 Safety in Users Guide.) Recommendations developed to date through this initiative are available at www.ashp.org/pharmacy-practice/standardize-4-safety-initiative.
Table 1: Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Morphine3635; 3636
| Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
| Adultsa | 1 mg/mL 5 mg/mL (based upon high dose requirements) | mg/hour |
| Pediatric patients (50 kg) | 0.2 mg/mL 0.5 mg/mL 1 mg/mL | mg/kg/hour |
a The S4S panel recommends trying to standardize dosing units but understands that some protocols may use “flat” dosing while others may require weight-based dosing.
Table 2: Standardize 4 Safety PCA Standard Concentrations for Morphine3990
| Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
| Adults | 1 mg/mL (caution is advised if both hydromorphone and morphine are used to avoid confusion in selection as both have the same concentration) 5 mg/mL 10 mg/mL | mg |
| Pediatric patients (50 kg) | 0.25 mg/mL 1 mg/mL (caution is advised if both hydromorphone and morphine are used to avoid confusion in selection as both have the same concentration) 5 mg/mL | mg/kg/hour |
Table 3: Standardize 4 Safety Epidural Standard Concentrations for Morphine as a Single Drug3990
| Patient Population | Concentration Standards |
|---|---|
| Adults | 0.5 mg/mL 1 mg/mL |
| Pediatric patients (50 kg) | 0.5 mg/mL 1 mg/mL |
Table 4: Standardize 4 Safety ADULT Epidural Combination Drug Standard Concentrations for Morphine3990
| Drug Combinations | Anesthetic Concentration | Narcotic Concentration |
|---|---|---|
| Bupivacaine with morphine | 1. Bupivacaine 0.0625% | 1. Morphine 0.5 mg/mL |
| 2. Bupivacaine 0.125% | 2. Morphine 1 mg/mL | |
| Ropivacaine with morphine | 1. Ropivacaine 0.1% | 1. Morphine 0.5 mg/mL |
| 2. Ropivacaine 0.2% | 2. Morphine 1 mg/mL |
Table 5: Standardize 4 Safety PEDIATRIC (50 kg) Epidural Combination Drug Standard Concentrations for Morphine3990
| Drug Combinations | Anesthetic Concentration | Narcotic Concentration |
|---|---|---|
| Bupivacaine with morphine | 1. Bupivacaine 0.0625% | 1. Morphine 0.5 mg/mL |
| 2. Bupivacaine 0.125% | 2. Morphine 0.5 mg/mL | |
| Ropivacaine with morphine | Ropivacaine 0.1% | Morphine 0.5 mg/mL |
Drugs in Syringe Compatibility
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Alprostadil
Alprostadil (Pfizer) 20 mcg/mL in dextrose 5% with morphine hydrochloride (Braun) 2 mg/mL in sodium chloride 0.9% protected from light was physically compatible for up to 4 hours at 22 to 25°C during a simulated Y-site administration study.3664; 3680
Bupivacaine Hydrochloride
Bupivacaine hydrochloride 25 mg/mL admixed with morphine sulfate 50 mg/mL in sterile water for injection appeared to prevent the formation of precipitation that occurs with morphine sulfate 50 mg/mL alone when refrigerated.2378
Bupivacaine hydrochloride 2.5 mg/mL admixed with morphine sulfate 5 mg/mL in sodium chloride 0.9% and bupivacaine hydrochloride 25 mg/mL admixed with morphine sulfate 50 mg/mL in sterile water for injection exhibited little or no loss of either drug in 60 days at 4 and 23°C. The slight yellow discoloration that appeared in the high concentration samples was not indicative of drug decomposition. Samples stored for 2 days at 37°C and frozen for 2 days at -20°C resulted in little or no loss of either drug. However, the frozen samples upon thawing exhibited the formation of large amounts of microparticulates numbering in the thousands per mL, possibly shed by the syringe components.2378
Clonidine Hydrochloride
Clonidine hydrochloride (Fujisawa) 100 mcg/mL and morphine sulfate (Elkins-Sinn) 10 mg/mL were mixed in equal quantities, transferred to flint glass vials with rubber stoppers, and stored for 14 days at controlled room temperature protected from light. The solutions remained clear and colorless with no increase in particulate content. Little or no change in the concentration of either drug occurred.2069
Clonidine hydrochloride 0.25 mg/mL admixed with morphine sulfate 5 mg/mL in sodium chloride 0.9% and clonidine hydrochloride 4 mg/mL admixed with morphine sulfate 50 mg/mL in sterile water for injection exhibited little or no loss of either drug at 4 and 23°C. The slight yellow discoloration that appeared in the high concentration samples was not indicative of drug decomposition. Samples stored for 2 days at 37°C and frozen for 2 days at -20°C resulted in little or no loss of either drug. However, a precipitate formed in the frozen samples as freezing occurred and in the refrigerated high concentration samples after 2 to 4 days. Upon warming to room temperature the precipitate redissolved, but the samples exhibited large amounts of undissolved microparticulates numbering in the thousands per mL remaining in the solutions, possibly shed by the syringe components.2380
For a list of references cited in the text of this monograph, search the monograph titled References.