Comparison of unusual administration methods of morphine

Comparison of unusual administration methods of morphine Morphine is a widely used analgesic. Its clinical use and the high dependency factor (morphine and heroin have proven to be the most addictive opiates) brought up the need to investigate the classic routes of administration (oral, rectal, iv, sc) and compare them with some not so well established routes (nebulised, intrathecal, transdermal, sublingual etc). Introduction Morphine is a strong opioid derived from the opium poppy, Papaver somniferum1. It is used for the management of moderate and severe pain. It acts directly to central nervous system exhibiting a quick time of action. Along with pain relief, it causes the sense of well being (euphoria). It can also produce a series of other central and peripheral effects such as sedation, cough suppression, nausea, constipation and might cause histamine release2. It is used during surgeries for anaesthesia and as a pain reliever after the operation. It is a drug of choice for terminal care and it is really useful for pain management in cancer patients3. Morphine is available at several formulations and different drug administration routes. The selection of the appropriate administration route is dependent on the extent of pain control required. For instance, parenteral morphine is used for acute severe pain, while oral morphine is used for the treatment of temporary pain. The location of the pain will also determine if it is necessary to apply topical preparations or not. Table 1 Pharmacokinetic Properties of three opioid analgesics Pharmacokinetic Parameters Half life Volume of Distribution Clearance Morphine (iv) 2-3 hours   3-5 litre/kg 15 -20ml/min/kg Fentanyl (iv) 3.5-3.8 hours 5-6 litre/kg 21-29ml/min/kg Diamorphine(iv) 2-3 minutes 25litre/kg Use morphine values Source: Clarkes analysis of drugs and poisons4 Moreover, pharmacokinetic parameters such as bioavailability, half life and clearance and other characteristics of the drug (table 1) like side effects, ADRs and interactions must be taken into account before choosing the appropriate drug route. Patients preference (or fear) for a specific drug route and other psychosocial factors might also affect the choice of the formulation and patients compliance and finally medicines effectiveness. Discussion Oral route Regarding oral route, morphine comes as a solution and as immediate or controlled (systained) release tablets and capsules(fig 2). Fig 2. Oral formulations of morphine Oral Suspension Morphine solutions come in different strengths. Oral solutions can be prescribed by writing the formula Morphine HCl 5mg and Chloroform water to 5ml but the proportion can be altered. Morphine Sulphate solutions (Oramorph) are available at 10mg/5ml and as concentrated solutions of 100mg/5ml3. Other excipients include: ethanol (96%- morphine is slightly soluble in ethanol), corn syrup, sucrose, methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216) and purified water. Due to the high content of alcohol this drug is not recommended to alcohol misusers. Normal adult dose is 10-20mg every four hours although when prescribed in palliative care dosage varies higher or lower according to the severity of the pain and kidney function respectively3. As this formulation is not readily absorbed from GI tract, in order to produce same effects as iv dose a 50%-100% increase in dose must be considered. Overdose risk is high and can cause hypotension, respiratory depression and in some cases death. Naloxone which is an opiate antagonist is the first line treatment in case of overdosing5. Tablets and Capsules Solid dosage forms contain morphine in form of salt e.g Morphine Sulphate and Morphine hydrochlorate. Theses salts in the body will be available as morphine bases. Tablets are available in two preparations immediate release and modified release. The short acting tablets come in 10mg, 20mg and 50mg3. They are given every 2-4 hours to control and stabilise breakthrough pain. These tablets are a way of determining the amount of morphine needed to manage pain. Once the quantity of morphine is established the patient can take slow-release tablets and capsules. These formulations contain enough morphine to control pain for 12 or 24 hours. The starting dose varies and from 10-20mg every 12hours if the patient has not taken any other painkiller previously, to 20-30 mg every 12 hours in cases of replacement weak analgesics3. Note only the dose can increase whereas the frequency must remain the same i.e. every 12 hours. It can take up to 48 hours for the morphine to reach the required plasma levels meaning that it is important to be taken regularly otherwise they lose their effectiveness5. If the patience experience pain between doses an additional dose must be given and the GP should decide if it is necessary to increase the daily dose. Oral morphine is a well established drug delivery method however; problems such as the first pass metabolism, the slow onset and the risk of overdose have raised questions on whether other novel administration routes can be used. Intravenous This route is used only in hospitals and in managing emergency pain symptoms. The bolus administration provides almost instant onset with a short effect. Iv morphine is used when sc route is not tolerated. A popular application of this method is in Patient Controlled analgesia (PCA) where the opioid is delivered using a Hospiral infusion device. The patient can control the morphine intake and establish an acceptable level of analgesia6. Morphine is available in 50 and 100ml vials with strength 1mg/ml3. It is used post operatively especially after transplants surgeries and in the management of chronic pain of malignancy. Although this method is useful for the management of severe pain there are many drawbacks. First of all, most of the pumps are bulky and invasive. Their installation is complicated as they require mains attachment and the patient has limited mobility .There is a high risk of overdose therefore supervision is needed. Side effects such as hypotension and respiratory dep ression might develop while convulsions due to high dosage are likely to occur. fig3. PCA infusion device vs syringe driver Subcutaneous Subcutaneous method is an excellent alternative to oral administration method. It is safe and effective method which is widely used both in palliative care and severe pain management. It is used for patients that present conditions such as gastrointestinal disturbances including indigestion, palindromic motility and obstruction5. A prime characteristic of the sc method is the syringe driver. The driver employs simple syringes and bears a flow rate setting option usually ml/hr which enables accurate dosing over a specific period of time. Unlike PCA infusion devices, it is battery powered, so patients mobility is not an issue (fig 3). The risk of overdose is lower compared to iv route as there is a constant stable administration schedule6. There is no need for continuous strict supervision as the driver is easy to use. Often, the subcutaneous route can cause some skin site problems. Irritation might appear especially when there are high concentrations of morphine or when it is combined with other drugs which are not fully compatible3. This problem can be treated either by diluting the dose or by choosing alternative more compatible drugs. Also some patients might experience needle allergic reactions and action must be taken e.g introduce an alternative Teflon cannula. Patients might feel discomfort, especially those who lack of subcutaneous tissue16. Sometimes, possible leakage of subcutaneous site might be observed. Finally, the sc method is not recommended for palliative care patients with acute vascular conditions. Rectal This drug administration route is quite popular and is used for short term management of acute pain. Also in terminal cancer patients modified release morphine sulphate is administered via this route6. Although the absorption rate varies for each individual, it is estimated that around 300-330 mg of morphine are absorbed rectally every four hours, indicating a sufficient analgesic effect. Studies have shown that for the patients who have never taken morphine, rectal morphine is more effective than the oral administered one5. Rectal morphine is available in the form of suppositories at different strengths (10, 15, 20 and 30 mg) 3. Prescribers must specify both the strength and the morphine salt (morphine hydrochloride or morphine sulphate) that suppositories should contain. Evidence shows two deaths15 after consequent doses of rectal morphine should raise awareness and the need of monitoring the dosing regimen and frequency. Rectal route is not avoiding completely the first pass metabolism; therefore the bioavailability might be influenced. Non conventional routes Apart from the conventional drug routes mentioned before, it is necessary to look into other not so popular ones such as the transmucosal, transdermal, sublingual, intrathecal and nebulised routes of administration and try to compare them. Transdermal- Transmucosal Transdermal route is a relatively painless method. The drug absorption is rapidly. Patches are easy to use and not quite expensive. Although this method is usually tolerated from the patients skin irritation and rashes might appear. Transdermal morphine is not popular as there are questions about the efficacy of this method. However, fentanyl another opioid is the drug of choice. More specifically, fentanyl patches are more effective in managing chronic pain compared to modified release oral morphine9. Also, transdermal fentanyl causes reduced constipation and drowsiness14. Another administration route which fentanyl is again preferred than morphine is the transmucosal route by a buccal tablet. The main reason is that fentanyl is a lipophilic drug while morphine has a limited lipid solubility. More specifically, when fentanyl is placed in saliva it is 80% non-ionized  and it usually takes 20-30 minutes for the analgesic effect to reach its peak14. Note transmucosal morphine is also available but the bioavailability is low and analgesic effect is not significant. Sublingual route This route utilises soluble immediate release tablets and it is recommended to patients that have swallowing difficulties. Morphine enters into bloodstream via sublingual mucosa. Investigations have shown that the absorption of morphine is the same (and in a few cases faster) compared with the oral route7. Same studies have shown that there is no significant difference in the extent and duration of analgesic effect when is compared with oral administered morphine3. Nebulised morphine Nebulised morphine utilises the airways to deliver the drug into pulmonary circulation. It can be used for COPD patients in the management of acute thoracic pain11. Through this route, the effect of hepatic metabolism is avoided and a rapid absorption is noted. However, the plasma drug levels are unpredictable indicating the necessity of further clinical investigations. Studies showed that inhaled morphine was as effective as intravenous PCA morphine without causing strong sedating symptoms8. Although nebulised morphine is well accepted, patients who are not used to opioids might experience nausea and vomiting and in rare cases respiratory depression. Other common side effects include constipation and histamine induced broncho-constriction. Another drawback of nebulised morphine is the high cost of the equipment (nebuliser, injectable vials, etc). It is not a simple method and some patients might find it difficult to use the nebuliser. Studies show a wide range of bioavailability in subjects; relating the bioavailability of the drug with the patients ability to use the nebuliser in the right way10. Epidural/intrathecal Both epidural and intrathecal routes are used mostly in the hospital clinical environment. The bioavailability is high so spinal administered morphine can provide extended analgesic effect at lower doses (compared to the conventional drug routes)12. Although epidural and intrathecal morphine can relieve both acute and chronic pain; studies suggest that these routes should be used only for pain which cannot be controlled by the classic established methods13. For instance, these routes are effective in managing lower body pain. Note that only 1% of the daily iv dose must be used intrathecally and only 10% epidurally5. An implanted infusion pump may be used to deliver intrathecal morphine at a continuous rate. A disadvantage of these methods is the high risk of infection and overdose as the staff must be trained and careful when dosing for breakthrough pains. Studies have reported a number of patients experiencing side effects such as sedation, dyspnoea, nausea and vomiting after spinal administration12. Spinal morphine is not usually preferred while diamorphine is the drug of choice due to its high solubility manner. Conclusion As it was mentioned before, morphine can be administered via different routes. However, it is vital each time to consider the risk- benefit ratio for each method and choose the most effective and safe one. Moreover, before establishing unconventional methods such as nebulised and spinal morphine it is important to further investigate their suitability and ways to improve the drug delivery and minimise side effects. Finally, if it is necessary to choose other opiates (such as fentanyl and diamorphine), which might be more efficient than morphine.