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Psychosomatics 40:185-192, June 1999
© 1999 The Academy of Psychosomatic Medine

Review

Nonenteral Routes of Administration for Psychiatric Medications

A Literature Review

Diane Thompson, M.D., and Andrea DiMartini, M.D.

Received July 17, 1998; accepted August 19, 1998. From the Magee Womens Hospital, 300 Halket Street, Pittsburgh, PA 15213. Address correspondence and reprint requests to Dr. Thompson at the same address.


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 SPECIFIC ROUTES OF...
 PSYCHOTROPIC MEDICATIONS
 CONCLUSIONS
 REFERENCES
 
In the treatment of psychiatric patients with complicating medical illness, clinicians may encounter patients who cannot take oral medications. This review will acquaint the practicing clinical psychiatrist with psychotropic medications available by nonenteral routes of administration. A computerized MEDLINE search was conducted of the literature 1981 to 1997. All articles citing nonenteral routes of psychotropic medication administration were reviewed. The results are summarized according to drug class and specific routes of administration (intravenous, intramuscular, sublingual, rectal). Psychotropic medications now available by these alternative routes are also listed in table form. The majority of the information available comes from small case series or case reports. Intravenous and intramuscular routes of administration of psychotropics are the most common. In addition, certain psychotropics are available by less common routes, such as sublingual or rectal administration. Consideration of alterations in pharmacokinetics, including poorer absorption and slower metabolism, are discussed. Clinicians may need to consider these novel routes of medication administration when dealing with patients unable to take oral medications.

Key Words: Psychotropics • Pharmacokinetics

  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
SPECIFIC ROUTES OF...
 PSYCHOTROPIC MEDICATIONS
 CONCLUSIONS
 REFERENCES
 
Administering psychiatric medications to patients unable to tolerate oral dosing or physiologically incapable of intestinal absorption creates a clinical dilemma for physicians treating such medically complicated patients. In the medical population, the prevalence of psychiatric illness can be great. For example, 30% to 50% of patients diagnosed with cancer meet criteria for a psychiatric illness.1 Nausea, emesis, nothing-by-mouth restrictions, or anatomical deficits, such as gastric or bowel dysfunction or resection, can prevent or delay treatment with oral medications. In these situations, withholding or delaying treatment with psychiatric medications and can cause significant distress to patients with a mental disorder and may not be necessary.

Currently, there is little published information and few clinical guidelines for alternative routes of administration for psychiatric medications. In addition to injectable psychotropic medications (see Santos et al.2 for a comprehensive review),we will focus on other less common routes of administration. This review will cover the availability of intravenous, intramuscular, sublingual, and rectal administration of antipsychotics, antidepressants, stimulants, mood stabilizers, and anxiolytics.

Most psychotropic medications are not specifically made for other than oral administration. Therefore, using such medications by alternative routes may significantly alter the expected pharmacokinetics of the oral preparation and may necessitate a pharmacologic alteration in the medication or vehicle of administration. For example, medications need to be in solution to passively diffuse through membranes. Many psychotropics (e.g., phenothiazines, tricyclic antidepressants, and many benzodiazepines) are weak bases and are best dissolved in the acidic stomach, where they are in an ionized form.3 Optimal absorption via passive diffusion occurs in the alkaline environment of the small intestine.4 If such a drug is administered sublingually or rectally, the required mucosal environment and pH (hydrogen ion concentration) in that area of the gastrointestinal tract may not be sufficient for dissolution or diffusion. Once absorbed, depending on the location of the vasculature and the site of administration, bypassing the effect of first-pass metabolism can cause a significant increase in bioavailability, compared with oral administration.5–7 The administration of medications via alternative routes must, therefore, be adjusted accordingly, as the bioavailability is increased or decreased.


  SPECIFIC ROUTES OF ADMINISTRATION

 
TOP
 ABSTRACT
 INTRODUCTION
 SPECIFIC ROUTES OF...
PSYCHOTROPIC MEDICATIONS
 CONCLUSIONS
 REFERENCES
 
Intravenous
Intravenous psychotropic medications have been widely used for decades for general anesthesia, sedating agitated patients, and relieving symptoms of anxiety. However, other than some phenothiazines, butyrophenones, and some benzodiazepines, most psychotropic medications, particularly the newer antidepressants, do not come in intravenous forms. In addition, though intravenous administration of an antipsychotic is a frequent clinical practice, it is not Federal Drug Administration-approved for psychiatric disorders.8 Good distribution by avoidance of first-pass metabolism are key factors in this route of administration. Difficulties occur with complications such as infiltration, risk of infection, and difficulty with venous access.

Intramuscular
This method is often used for rapid tranquilization in an emergency setting because of fast absorption and increased bioavailability.9 Depot antipsychotics are also administered intramuscularly. Their rate-limiting step is the release of the medication from the depot solution, which is dependent on the amount of subcutaneous fat. In addition, first-pass metabolism is avoided.5 In patients with reduced muscle perfusion, such as in cardiac insufficiency, intramuscular injections should be avoided. Daily injections of tricyclics or antipsychotics may be undesirable to the patient and may also lead to muscle irritation, necrosis, or abscesses.

Sublingual/Buccal
The abundance of sublingual capillaries, their proximity to the mucosal layer, and the efficacy of sublingual medications such as nitroglycerin suggest this route as a possible option for psychotropic medication administration. Although minimal research has been done, this may be an effective route, especially for nonionized, highly lipid-soluble medications. Pharmacokinetic models show that increasing the concentration of the nonionized, lipid-soluble form of the drug increases the percentage of buccal drug absorption.10 Haloperidol, chlorpromazine, clomipramine, diazepam, nitrazepam, promethazine, and trihexyphenidyl are examples of nonionized, highly lipophilic drugs11 that may diffuse across the mucosal membranes at physiologic pH (pH 7.4). Venous drainage via the oral mucosa is superior to the vena cava and avoids first-pass hepatic metabolism completely.12 Patients with severe nausea, such that any oral stimulation is intolerable, may not benefit from this form. In addition, many medications may have a bitter taste, creating further nausea.

Rectal
Patients who will not tolerate any gastric stimulation may benefit from a medication that can be absorbed rectally. This may be particularly useful for patients who cannot tolerate sublingual medication and for those who are not likely to tolerate daily intramuscular or intravenous dosing. The absorption is expected to be somewhat incomplete with rectal administration. The drug preparation and vehicle are important with hydrophilic solutions, resulting in improved absorption.13 Larger volumes increase the bioavailability by increasing the mucosal surface in contact with the drug,13 though a larger volume enema may be uncomfortable for the patient. As with buccal absorption, only the nonionized moiety of a drug will be available for transmucosal diffusion, and this will be affected by the pH of the rectum.13 For enema administration, the pH of the solution can be increased to improve absorption, as long as the rectal mucosa is not irritated. A substantial portion of the venous drainage from the perivascular rectal plexus travels through the rectal veins to the iliac veins and ultimately enters the inferior vena cava, thereby avoiding the portal vein and first-pass hepatic metabolism. Fifty percent of a rectally absorbed medication will bypass first-pass metabolism in the liver.3 Patients may prefer suppository forms of medication to enemas.


  PSYCHOTROPIC MEDICATIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 SPECIFIC ROUTES OF...
 PSYCHOTROPIC MEDICATIONS
CONCLUSIONS
 REFERENCES
 
There is limited clinical experience on the administration of psychotropic medications by nonenteral routes, and the information available comes from case reports and small clinical trials. Most of these medications are available in the United States, although not necessarily approved for psychiatric administration by alternative routes. Medications available in other forms in other parts of the world are also briefly discussed. In some cases, psychotropic medications were specially compounded by pharmacists to allow administration by a novel alternative route.

Antipsychotics
Though several antipsychotic medications are listed as having intravenous preparations, only intravenous haloperidol is described in the literature for use in the treatment of psychosis and agitation.14–16 In the case of haloperidol, pharmacokinetics play a significant role—40% less is available via the oral route, compared with intravenous administration.17 Cardiovascular or neurologic complications from intravenous haloperidol were not noted in one study of patients with cardiac disease,14 though QT interval prolongation and Torsades de Pointes arrhythmia were described in three patients receiving intravenous haloperidol.18 These three patients had cardiac disease, dilated cardiomyopathy, and histories of longstanding alcohol abuse. The authors recommended the use of intravenous haloperidol be accompanied by cardiac monitoring (at least baseline electrocardiogram (ECG), measurement of QT and QTc intervals, and ECG reassessment on haloperidol) and the assessment for risk factors such as alcohol abuse or cardiac disease.15 Extrapyramidal side effects occur less frequently with intravenous administration.14,19 Droperidol is also available in intravenous form and is more sedating than haloperidol. However, because droperidol is rapidly absorbed from the site of injection, the response to intramuscular is difficult to distinguish from intravenous administration.8 The risk of hypotension (due to greater peripheral alpha-adrenergic blockage) may limit the use of droperidol in the medically compromised.

Antidepressants
While the tricyclic antidepressant clomipramine is available in intravenous form in Europe, it and all other antidepressants are not widely available in forms other than oral in the United States. There are few case reports of rectal administration and no reports of sublingual use. Intramuscular and intravenous administrations have been used but are not currently available in the United States. Of additional interest, animal studies have shown that down-regulation of beta-adrenergic receptors, which may be involved in therapeutic response, can rapidly be achieved by intravenous infusion.20,21

The use of amitriptyline and cocoa butter in a 50-milligram suppository was reported to improve mood and sleep in a woman with colonic adenocarcinoma.22 Amytriptyline serum levels were not measured. A second report of tricyclic suppositories consisted of four patients who received doxepin capsules with no suppository base in 25-milligram form. The patients received up to 50 milligrams, and three of the four had therapeutic levels after 2 to 5 days at their maximum dose.23 The authors noted improvement in neuropathic pain but did not assess depressive symptoms.

Intravenous clomipramine has been used in several studies, including a randomized trial of oral vs. pulse-loading intravenous clomipramine.24 Twenty-two hospitalized patients with a major depressive disorder were given either a 150-milligram dose of clomipramine hydrochloride intravenously or a 150-milligram oral dose. An increased dose of 200 mg was repeated 24 hours later. Five days later, a significant improvement was noted in both groups on the Hamilton Depression Rating Scale, the Raskin Severity for Depression Scale, and the Beck Depression Inventory.

Intramuscularly administered imipramine was compared with the oral form in 18 depressed hospitalized patients.25 Two mg/kg/day were administered intramuscularly for 14 days. On Day 14, the mean plasma concentrations for imipramine were between 82±8.5 ng/ml to 112.2 ±8.0 ng/ml. Oral imipramine was then administered from Day 15 to Day 21. The daily dose had to be doubled to maintain the plasma levels reached with the intramuscular dose.

We recently administered fluoxetine enemas to a patient with major depression who has no stomach or small intestine (unpublished data). Fluoxetine (20 mg in 30 cc of sterile water) was administered rectally once in the morning. Pharmacokinetic studies demonstrated absorption, though serum levels remained subtherapeutic at 1, 3, 6, 12, and 18 hours postadministration (fluoxetine range: 30–40 ng/mL and norfluoxetine range: 37–43 ng/mL during the 18-hour period). Though she experienced some improvement in mood and affect, she did not have a complete clinical response. In addition, as the dosage was increased, she was unable to tolerate the enemas because of abdominal cramping that occurred shortly after administration and persisted for several hours after dosing. We believed the cramping was caused by introduction of air into the colon, the isotonic solution, or the serotonergic features of fluoxetine.

Newer classes of antidepressants, including buproprion, venlafaxine, and mirtazapine, have no data on alternative routes of administration. Similarly, the monoamine oxidase inhibitors are only available in oral form, and there are no reports of administering via a different route in U.S. studies. However, as with several other medications, the monoamine oxidase inhibitor moclobemide was administered in both the oral and intravenous form in a comparative study in Europe.26 Intravenous citalopram, a selective serotonin reuptake inhibitor, is available in Europe for use in treatment-resistant depression. Infusions of 20 mg, increased to 40 mg, are followed in 10–14 days, with oral therapy based on the same dosage.27 Other novel routes of administration such as topical application are now being explored, but additional data are not yet available on these innovative alternatives.

Psychostimulants
Psychostimulants are being used for medically ill patients and have been shown to be an effective treatment for depression28–30 and as an adjuvant to narcotic analgesics.31 The recommended route for stimulant medication is oral, though two case reports suggest buccal absorption and suppository form may also be effective. Intravenous forms have also been used for research purposes.

The first study reported describes the use of pemoline in four patients.32 In two of the cases, the authors describe the administration via buccal absorption. In the first case, a woman with intermittent bowel obstruction was given pemoline in a chewable tablet that could be absorbed from the buccal mucosa. Her dose was titrated to 37.5 milligrams bid, and improvement in mood and energy was noted in 4 days. The next case concerned a man with gastric cancer. He was given a 37.5-milligram tablet of pemoline to suck on and instructed to dissolve the tablet in his mouth. His dose was also increased to 37.5 milligrams twice a day, with improvement in affect and concentration.

Beckett et al. evaluated buccal absorption of stimulants at varying pH.33 Male subjects were given a 25-milliliter solution of amphetamine, methylamphetamine, or dimethylamphetamine. They were instructed to hold the solution in their mouths for 5 minutes without swallowing and to circulate it about once/second (perhaps to increase contact with the mucosa). The researchers found superior absorption of these drugs at a high pH (9.18), with a range of 68.5 % to 88.5% absorption.

Another report describes the use of dextroamphetamine suppositories in a woman with gastrointestinal obstruction.34 Dextroamphetamine suppositories in 5-milligram form were devised by the pharmacy and administered in the morning. Though the milligram dosage used was not specified, the author notes significant improvement in the patient's mood and affect. Symptoms recurred with discontinuation of the stimulant and abated once the medication was resumed.

Methylphenidate has been abused intravenously and can result in pulmonary disorders attributable to pill fragments.35,36 An intravenous form is not commercially available; however, it has been used for research purposes. A 1985 study found no relationship between an initial response to intravenous methylphenidate and response to zimeldine, a relatively serotonergic antidepressant.37 Fifteen depressed patients received 0.3 milligram of intravenous methylphenidate per kilogram body weight. They were assessed 50 minutes later by the author and self-reports. Nine had a positive response, five had a negative response, and one experienced no change. The self-reports were based on four scales that assessed happy/sad, lethargic/energetic, unfriendly/friendly, and mind blank/racing. The author also rated the subjects according to a global change in mood. No untoward events were noted.

Though not used for psychiatric purposes, intravenous D-amphetamine was administered with placebo, pimozide, or lithium to determine effects on norepinephrine, dopamine-beta-hydroxylase, pulse rate, and blood pressure in schizophrenic patients.38 Twenty milligrams of D-amphetamine were given intravenously. Norepinephrine increased by 188±56 pg/ml; however, the dopamine-beta-hydroxylase did not change significantly. Pulse rates with D-amphetamine increased by a mean of 11±20 beats per minute, and both systolic and diastolic blood pressure were significantly increased. The mean systolic change was 26±25 torr, and the mean diastolic change was 10±12 torr. While there were no medical complications recorded, it is important to note that neither of these studies included medically compromised patients, who may not tolerate the cardiovascular changes.

Mood Stabilizers
Lithium, valproate, and carbamazepine are the current medications available in nonoral forms for stabilization of mood. Lithium is only available in oral form in the United States. Lithium oligosol is a sublingual medication that achieves detectable plasma levels in patients in Europe.39 Studies with intravenous lithium and intraperitoneal lithium offer other possibilities. A case report demonstrates that intraperitoneal lithium can be administered to bipolar patients with end-stage renal disease.40 In this report, lithium was first used intramuscularly, but there are no details of administration. The procedure for the intraperitoneal lithium solution consisted of dissolving 89 milligrams of lithium chloride in 5 milliliters of sterile water, which was filtered and collected so that each milliliter contained 17.8 milligrams of lithium chloride. Eighty and one-tenth milligrams were added to every two-liter bag of dialysate. There was an improvement in mania with the treatment, and serum lithium correlated well with dialysate lithium. Lithium clearance of 10 to 15 milliliters per minute approximates normal renal function.

Another 1987 study used intravenous lithium to determine its effect on cerebral electrical activity.41 A 41-year-old, bipolar patient received lithium 15 milliliters twice a day for 10 days. On Day 10, the plasma concentration was 0.85 mm/L, and the erythrocyte concentration was 0.13 mm/L. The authors note no clinical neurotoxicity, but a slowing of electroencephalogram activity was observed with the lithium monotherapy.

Although there are no known studies on the use of valproic acid suppositories and retention enemas for mood stabilization, they have been used for treatment of status epilepticus.42,43 The serum concentration of valproic acid in a rectal suppository was compared with the oral dose in six males.44 The mean absorption was 80%; however, it took 3.1 hours for the suppository to reach maximum concentration vs. 1 hour for the oral form. The serum concentration of equivalent doses (500 milligrams) was 43.4 milligrams per liter in the oral dose and 29.2 milligrams per liter for the suppository.

A similar study was done with rectally administered carbamazepine vs. oral administration in healthy subjects.45 While rectal absorption was slower, the bioavailability was similar. The authors concluded that the suppository can be given in doses equivalent to the oral form. Another report describes the use of carbamazepine, doxepin, or both in six cancer patients with severe pain or seizures. The carbamazepine was crushed, placed in gelatin capsules, and inserted into the rectum. At doses of 600 milligrams bid or tid, five of the six patients reached therapeutic levels; all showed clinical improvement.20 There were no further seizures in the two patients with prior seizures, and the patients were more comfortable.

Abbott Laboratories now have valproate sodium injection for the treatment of partial and complex seizures. The intravenous administration was developed for patients who cannot take the oral form.46 This approach may be a promising alternative for medically ill patients who were taking valproate sodium for mood stabilization, and now are not able to take oral medications.

Anxiolytics
While there are no reports of nonenteral routes for buspirone, there are several benzodiazepines that can be administered intramuscularly or intravenously. There are a few reports on the use of sublingual benzodiazepines and many on rectal administration of benzodiazepines. Nasal administration of short-acting benzodiazepines (midazolam) are used for preanesthetic or anesthetic medication and can even be safely used in children.47 This route for psychiatric purposes is not reported.

A review paper on the rectal administration on diazepam concludes that this is an excellent alternative for the management of seizures.48 The author reviewed eight papers, which concluded that rectally administered intravenous diazepam reaches therapeutic levels in 5 to 10 minutes. Therapeutic levels were between 754 ng/mL and 98.5 ng/mL and were based on seizure control. According to this review, the recommended administration is undiluted diazepam intravenous solution inserted with a small syringe.

Sublingual administration is reported infrequently, but three papers on alprazolam and lorazepam indicate that this is an effective route. The pharmacokinetics of sublingual lorazepam were compared with intravenous, intramuscular, and oral lorazepam in 10 subjects.49 For sublingual and oral administration, patients were asked to fast overnight and then received two standard 1-milligram tablets that were held under the tongue for 15 minutes. Blood samples were drawn at 5 minutes and then at intervals up to 48 hours for the 10 subjects. The mean peak plasma concentration was 23.3 ng/mL for the sublingual dose vs. 24.9 ng/mL for the oral dose. Peak concentration occurred at 2.35 hours for the sublingual and 2.37 hours for the oral dose. The systemic availability was 94.1% sublingual and 99.8% oral. The authors conclude that sublingual lorazepam, given on an empty stomach, could be substituted for both oral and intramuscular lorazepam.

The kinetics of oral and sublingual alprazolam were studied in 13 fasting volunteers.50 A 1-milligram tablet was used for both the oral and sublingual administration, and blood samples were drawn at 5 minutes and then throughout a 48-hour period. The mean peak plasma concentration for the sublingual dose was 17.3 nanograms per milliliter and 14.4 nanograms per milliliter for the oral dose. Time of peak concentration was 1.17 hours sublingually and 1.73 hours orally. As with lorazepam, sublingual alprazolam is basically equivalent to the oral dose.

A third mention of sublingual lorazepam or alprazolam is from a letter to the editor and describes one author's experience.51 The author concludes that lorazepam or alprazolam tablets chewed or held under the tongue give patients relief from panic symptoms in as few as 2 minutes. There is no discussion of sample size or pharmacokinetics.


  CONCLUSIONS

 
TOP
 ABSTRACT
 INTRODUCTION
 SPECIFIC ROUTES OF...
 PSYCHOTROPIC MEDICATIONS
 CONCLUSIONS
REFERENCES
 
Antipsychotics, antidepressants, stimulants, mood stabilizers, and anxiolytics all have some alternative route of administration, though some preparations are not yet available in the United States. Intravenous and intramuscular routes are more commonly used but must be adjusted for first-pass metabolism or alterations in muscle perfusion. Though incomplete ionization and a different mucosal environment are expected to impede the absorption of rectally or sublingually administered oral medications, the therapeutic levels and clinical response of medications delivered by these routes suggests that the pH of the environment, while important, may not be critical. When available, blood levels should be monitored to determine absorption. Even when therapeutic levels are not available, we have used blood levels to determine if absorption has occurred.

With increasing clinical experience, the availability of newer options is being explored. Nasal administration of midazolam is possible and perhaps could be extended to other benzodiazepines. Patches used for the administration of narcotic analgesics may also provide a possible route of administration. In some cases, pharmacists have worked with the treating physician to compound psychotropic medications for novel alternative routes. For example, topical administration of psychotropics is now being investigated, though not enough information exists to recommend this route. However, the currently available alternatives, as outlined in Table 1, provide many useful options for the treatment of those persons who are not able to take oral medication.


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TABLE 1.Psychiatric medication and routes of administration




  REFERENCES

 
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 INTRODUCTION
 SPECIFIC ROUTES OF...
 PSYCHOTROPIC MEDICATIONS
 CONCLUSIONS
 REFERENCES
 

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