ALTERNATIVES TO THE ORAL DELIVERY OF OPIOIDS

This section summarizes the advantages and disadvantages of alternative methods of opioid delivery including the subcutaneous, rectal, intravenous, transdermal, intraspinal, transmucosal, intranasal and topical routes.

Primary references used are listed below. Secondary references are listed with each route. Effective use of alternative routes can only be done safely with knowledge of equianalgesic dosing, a topic not covered here.


SUBCUTANEOUS

OPIOIDS USED SUBCUTANEOUSLY
Morphine, hydromorphone, diamorphine (UK), methadone, levorphanol, fentanyl, sufentanil.

METHOD OF DELIVERY

  • A butterfly needle can be inserted in the patient's anterior chest or abdomen or a plastic cannula can be used to avoid multiple injections.
  • Subcutaneous continous infusions can be made with a variety of portable pumps for inpatients and with portable battery-operated pumps or syringe drivers for outpatients.
  • Subcutaneous administration can be intermittent for incident pain; this simple technique does not require infusors or pumps, but the patient or family must be trained to draw up the opioid solution into the rubber gasket of the butterfly tubing.

ADVANTAGES

  • Simple, safe and effective;
  • Venous access is not required;
  • Close supervision is unnecessary;
  • Infection is unlikely;
  • Continuous subcutaneous infusion is well suited for long-term use by ambulatory outpatients;
  • Suited for home care;
  • Continuous subcutaneous infusion reduces the peaks and valleys in plasma opioid concentration, making this route effective in treating pain in advanced cancer;
  • Also used for long-term hydration.

DISADVANTAGES

  • May not be practical in patients with generalised edema, in patients who develop erythema, soreness, or sterile abscesses with subcutaneous administration, in patients with coagulation disorders, in patients with poor peripheral circulation. In these patients, intravenous administration is preferred;
  • Contraindicated with subcutaneous methadone because of adverse skin reactions.

COST

  • In countries with limited resources, syringe pumps or low-cost injector devices (eg, Edmonton Injector) can provide subcutaneous delivery at lower cost;
  • Subcutaneous hydromorphone is less costly than morphine infusion;
  • In the US, the cost of delivering subcutaneous morphine by syringer driver is twice the cost of a comparable dose of sustained release tablets.

REFERENCES
Primary references are listed below.

Fudin J, Smith HS, et al. Use of continuous ambulatory infusions of concentrated subcutaneous hydromorphone versus intravenous morphine: cost implications for palliative care. Am J Hosp Palliat Care 2000; 17(5):347-353.



RECTAL

OPIOIDS FOR RECTAL USE

  • Morphine, oxymorphone, oxycodone, hydromorphone and methadone; commercial availability varies by country.
  • Controlled-release morphine sulfate hydrogel suppository with a 24-hour duration of effect available in the UK;
  • Immediate-release tablets can also be placed in a gelatin capsule and made into suppositories.

ADVANTAGES

  • Action is independent of gastrointestinal tract;
  • Allows the opioid to enter the systemic circulation via lower rectal veins;
  • Indicated in patients with nausea, vomiting, dysphagia, bowel obstruction or malabsorption;
  • Useful when patients are fasting before or after surgery;
  • Alternative to injections in patients with bleeding disorders or generalized edema;
  • Useful when infusion techniques are not available;
  • Absorbed into systemic circulation as readily as oral morphine;
  • Duration of analgesia is the same as with oral route;
  • Easy to administer for unskilled caregivers;
  • Hospital pharmacies can prepare suppositories in any strength.

DISADVANTAGES

  • Considerable individual variability in the absorption of rectal opioids;
  • Necessary dose varies a great deal among individuals, requiring careful individual titration;
  • Absorption of drug depends on preparation (aqueous, or alcoholic solutions, suppositories), pH of solutions used and presence of feces in rectum;
  • Cannot be used in patients with diarrhea, a colostomy, hemorrhoids, anal fissures or neutropenia;
  • Prolonged use is not recommended because it is uncomfortable and the expulsion of the suppository by bowel movement will affect drug absorption;
  • Mode of administration disliked by caregivers and/ or patients in some cultures.

REFERENCES
Primary references are listed below.

Walsh D, Tropiano PS. Long-term rectal administration of high-dose sustained-release morphine tablets. Support Care Cancer 2002; 10: 653-655.



INTRAVENOUS

OPIOIDS USED INTRAVENOUSLY
Morphine, hydromorphone, fentanyl, sufentanil and methadone.

ADVANTAGES

  • Intravenous (IV) opioid infusions can be given either as continuous infusion or with a patient-controlled analgesia (PCA) device which allows on-demand boluses;
  • Provides the most rapid onset of analgesia;
  • Provides a consistent level of analgesia;
  • Allows the patient to receive a continuous infusion of the opioid;
  • Helps in identifying opioid nonresponsive pain quickly so other pain control strategies can be considered early;
  • Useful in patients whose pain cannot be relieved by a less invasive route;
  • Useful in patients who require rapid incremental doses of opioids due to pain emergencies or breakthrough pain;
  • Preferred in patients who already have an indwelling intravenous line;
  • Preferred in patients with generalized edema, coagulation disorders, or poor peripheral circulation;
  • Allows outpatients to be discharged home quickly with good pain control.

DISADVANTAGES

  • Requires prolonged venous access via central or peripheral catheter;
  • Local irritation of skin may occur;
  • Intravenous catheters can lead to infection;
  • Intravenous catheters are complicated to maintain;
  • Requires initial close supervision, and continuity of skilled medical and nursing care;
  • Puts a burden on the family in terms of equipment, learning how to administer medications and associated costs.

COST
Costs are associated with:

  • placement of a permanent intravenous access;
  • preparation of the opioid solution by the pharmacist;
  • administering the infusion via an external pump;
  • nursing support for outpatients.

REFERENCES
Primary references are listed below.

Mercadante S. Intravenous morphine for pain emergencies. Poster presented at 8th Congress of the European Association for Palliative Care, The Hague, The Netherlands, April 2003.

Kumar S, Rajagopal MR, Naseema AM. Intravenous morphine for emergency treatment of cancer pain. Palliat Med 2000; 14: 183-188.

Elsner F, Sabatowski R, Radbruch L. Emergency pain treatment - ambulatory intravenous morphine titration in a patient with cancer pain. Anasthesiol Intensivmed Notfallmed Schmerzther 2000; 35: 462-464.



TRANSDERMAL

TRANSDERMAL OPIOIDS
Fentanyl, buprenorphine (Europe).

METHOD OF DELIVERY
A reservoir of the drug and alcohol contains a 3-day supply. The drug reservoir is covered by a permeable membrane that controls the rate of release of the drug into the skin; an adhesive layer holds the delivery system in place; the drug is released at constant rate. Passive diffusion through the skin brings the active drug into the blood stream where it is transported to its target receptors.

ADVANTAGES

  • Simple, well-tolerated method that produces stable blood concentrations;
  • Good option for long-term administration of strong opioids;
  • Convenient;
  • Long duration of action;
  • May improve patient compliance by lessening the need to take a medication by mouth on a regular basis;
  • Useful when patients have severe constipation;
  • Multiple patches may be placed if higher doses are needed;
  • Some patients experience less constipation when treated with transdermal fentanyl than with oral morphine;
  • Some patients experience improved quality of sleep.

DISADVANTAGES

  • Only a few highly soluble drugs can be administered transdermally for absorption through the skin;
  • Inappropriate for patients who need frequent dose changes or rapid dose titration;
  • Appropriate only for patients with a stable pain condition;
  • Appropriate only for patients who are opioid-tolerant;
  • Less flexible to administer than shorter-acting opioids;
  • Less useful in patients with generalized edema;
  • Patients on transdermal opioids require an oral or transmucosal rescue dose of short-acting opioid for breakthrough pain.

REFERENCES
Primary references are listed below.

McNamara P. Opioid switching from morphine to transdermal fentanyl for toxicity reduction in palliative care. Palliat Med 2002; 16(5):425-434.

Ellershaw JE, Kinder C, Aldridge J, Allison M, Smith JC. Care of the dying: is pain control compromised or enhanced by continuation of the fentanyl transdermal patch in the dying phase? J Pain Symptom Manage 2002; 24(4):398-403.



INTRASPINAL

OPIOIDS FOR SPINAL DELIVERY

  • Morphine, hydromorphone, fentanyl, sufentanil and meperidine.
  • Diamorphine (UK).

METHOD OF DELIVERY

  • Small doses of the opioid are delivered close to their receptors in the dorsal horn of the spinal cord, resulting in high local concentration.
  • Fine catheters are placed within the epidural space or within the cerebrospinal fluid in the subarachnoid space.
  • Catheters may be tunnelled subcutaneously to exit under the skin at an accessible site. They are attached to a bacterial filter for intermittent or continuous drug administration or, alternatively, may be connected to a subcutaneously implanted reservoir or pump delivery system, which can function for weeks or months.
  • The opioid may be delivered by intermittent bolus or by continuous infusion, with similar efficacy.

ADVANTAGES

  • Produces prolonged analgesia, increases patient alertness;
  • Has fewer side effects than systemic opioid administration;
  • Requires lower doses than systemic opioid administration;
  • A spinal catheter can be implanted on a temporary basis to make sure the patient can benefit from the drug before the system is made permanent;
  • The patient or a family member can be taught to inject the drug through the catheter port in a sterile manner;
  • Treatment is reversible and can be adjusted as needed;
  • Weak solutions of local anesthetics (eg, bupivacaine, lidocaine) or of the alpha-2 agonist clonidine can be added to provide relief for resistant neuropathic pain.

DISADVANTAGES

  • Risk of infection of the epidural space;
  • Risk of mechanical failure of the drug delivery system: implanted catheters can become plugged, may kink or break;
  • Catheters may migrate out of the subarachnoid or epidural space;
  • Implanted reservoirs or pumps occasionally become disconnected from the catheter;
  • Sophisticated method of delivery requiring anesthesiologist with advanced training in pain management;
  • Requires the presence of a home-care nurse to handle technical problems;
  • Intraspinal delivery demands more of patients and caregivers than oral medications;
  • Only appropriate in a small population of patients who have a remaining life span of at least 3 to 6 months;
  • Only appropriate if patients derive inadequate pain control or suffer intolerable side effects after escalation of treatment with systemic opioids;
  • Implantable catheters cannot be given to a patient who lives in a rural, medically underserved area or who has difficulty accessing a medical facility that can have the catheter refilled or reprogrammed.

COST

  • External pumps are cheaper than implanted ones for short-term use, but more expensive when used for more than a few months;
  • An implanted pump system, while more costly than oral opioids, can be cost effective long term, when compared to the use of a spinal catheter connected to an external pump.

REFERENCES
Primary references are listed below.

Mercadante S. Problems of long-term spinal opioid treatment in advanced cancer patients. Pain 1999; 79(1):1-13.



TRANSMUCOSAL AND SUBLINGUAL

TRANSMUCOSAL OPIOIDS
Buprenorphine, fentanyl, sufentanil and methadone.

METHOD OF DELIVERY
The opioid is absorbed through mucous membranes in the inner cheeks' walls and the sublingual area. Saliva aids drug dissolution.

ADVANTAGES

  • Administration is simple;
  • Requires little expertise, preparation, or supervision;
  • Good sublingual absorption for highly lipophilic drugs;
  • More rapid absorption than oral route;
  • Faster onset of pain relief than oral route;
  • Useful in patients who lack venous access, are emaciated, or have coagulation problems;
  • Useful in dying patients no longer able to swallow;
  • May be a useful alternative to low-dose oral morphine for patients who have difficulty swallowing;
  • Effective for breakthrough pain;
  • Well tolerated;
  • High patient satisfaction.

DISADVANTAGES

  • Unpleasant bitter taste of most opioids;
  • Difficulty knowing how much drug is absorbed and how much is swallowed reflexively;
  • Not useful in patients with cognitive impairment;
  • Sublingual absorption of morphine is slow.

REFERENCES
Primary references are listed below.

Gardner-Nix J. Oral transmucosal fentanyl and sufentanil for incident pain. J Pain Symptom Manage 2001; 22:627-630.



INTRANASAL

OPIOIDS FOR INTRANASAL DELIVERY
Diamorphine (UK), fentanyl, sufentanil, morphine.

METHOD OF DELIVERY
Spray device delivers opioid dose as a fine spray to the nasal mucosa.

ADVANTAGES

  • Convenient and easy to administer;
  • Provides rapid absorption of lipophilic opioids;
  • Fast onset of pain relief;
  • Appears to be a useful option for management of breakthrough pain.

DISADVANTAGES

  • Little is known about analgesia associated with nebulized/aerosol delivery;
  • Cannot be used by patients with cognitive impairment;
  • Not useful for patients with respiratory failure;
  • Not useful for patients who are extremely ill, comatose, suffer asthma, or claustrophobia;
  • Morphine is poorly absorbed via the nasal mucosa;
  • Not enough evidence of clinical advantage over conventional routes.

REFERENCES
Primary references are listed below.

Kendall CE, Davies AN, Forbes K. Nasal diamorphine for breakthrough pain in palliative care: A promising approach to a difficult problem. Poster presented at 8th Congress of the European Association for Palliative Care, The Hague, The Netherlands, April 2003.

Jackson K, Ashby M, Keech J. Pilot dose- finding study of intranasal sufentanil for breakthrough and incident cancer-associated pain. J Pain Symptom Manage 2002: 23(6): 450-452.



TOPICAL

OPIOID FOR TOPICAL USE
Morphine.

METHOD OF DELIVERY
Topical morphine is given as a gel, the amount of gel depending on the size and the site of the ulcer; the gel is kept in place with gauze coated with petroleum jelly or a non-absorbent dressing.

ADVANTAGES

  • Useful to relieve persistent pain due to ulcerative skin lesions (eg, Karposi's sarcoma lesions in people with AIDS, lesions related to melanoma and other cancers);
  • Useful in patients with cutaneous pain due to tumor infiltration;
  • Used to treat oral mucositis pain;
  • Provides rapid relief of pain;
  • Beneficial for pain of pressure ulcers.

DISADVANTAGES

  • Lack of evidence about onset of analgesia, duration of pain relief, degree of systemic opioid absorption and site of opioid action with topical administration.

REFERENCES
Primary references are listed below.

Cerchietti LC, Navigante AH, Bonomi MR et al. Effect of topical morphine for mucositis-associated pain following concomitant chemoradiotherapy for head and neck carcinoma. Cancer 2002; 95(10):2230-2236.

Krajnik M, Zylicz Z, Finlay I, Luczak J, van Sorge AA. Potential uses of topical opioids in palliative care--report of 6 cases. Pain 1999; 80(1-2):121-125.

Twillman RK, Long TD, Cathers TA, Mueller DW. Treatment of painful skin ulcers with topical opioids. J Pain Symptom Manage 1999;17(4):288-292.



PRIMARY REFERENCES

American Pain Society. Guideline for the Management of Cancer Pain in Adults and Children (in press).

Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: An evidence-based report. J Clin Oncol 2001; 19 (9):2542-2554.

Donnelly S, Davis MP, Walsh D, Naughton M. Morphine in cancer pain management: a practical guide. Support Care Cancer 2002; 10: 13-35.

Hanks GW, Conno F, Cherny N et al. Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001; 84(5):587-593.

Stevens RA, Ghazi SM. Routes of opioid analgesic therapy in the management of cancer pain. Cancer Control 2000; 7 (2): 132-141.

Twycross R, Wilcock A. Symptom management in advanced cancer. Third edition. Abingdon, UK: Radcliffe Medical Press, 2001.

Twycross R, Wilcock A, Charlesworth S, Dickman A. Palliative Care Formulary. Second Edition. London: Radcliffe Medical Press Ltd., 2002.

World Health Organization. Cancer Pain Relief. Second Edition. With a guide to opioid availability. Geneva: World Health Organization, 1996.