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Phase Ia and Ib Study of Amitriptyline for Ulnar Nerve Block in Humans

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Phase Ia and Ib Study of Amitriptyline for Ulnar Nerve Block in Humans Anesthesiology 2004; 100:1511–8 © 2004 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Phase Ia and Ib Study of Amitriptyline for Ulnar Nerve Block in Humans Side Effects and Efficacy Peter Fridrich, M.D.,* Sunil Eappen, M.D.,† Walter Jaeger, Ph.D.,‡ Eva Schernhammer, M.D., Dr.P.H.,§ Anthony M. Zizza, B.A.,ʈ Ging Kuo Wang, Ph.D.,# Peter Gerner, M.D.† Background: The antidepressant amitriptyline is used as an with opioid and adenosine receptors.8 In addition, ami- adjuvant in the treatment of chronic pain conditions. Among its ؉ triptyline has been shown to block various voltage-gated many actions, this drug also blocks ion channels, such as Na ϩ ϩ ϩ ion channels, including Na ,K , and Ca channels.9–12 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/100/6/1511/356212/0000542-200406000-00025.pdf by guest on 27 September 2021 channels. Preliminary animal studies suggested that amitripty- ϩ line would be a longer-lasting local anesthetic than bupiva- Because blocking Na channels is a major feature of caine, with potentially fewer side effects. Therefore, the authors local anesthetics, it was hypothesized that amitriptyline investigated the adverse effects and effectiveness of this drug may have local anesthetic properties. Further experi- when given for ulnar nerve blockade in human volunteers. mentation has shown that amitriptyline has greater effi- Methods: After obtaining written institutional review board cacy than both lidocaine and bupivacaine when used to approval and informed consent, a typical phase Ia trial was 13 conducted by administration to the ulnar nerve at the level of produce sciatic nerve blockade in rats. the wrist in an open-label, dose-escalating fashion. Amitripty- To date, there has been no report on the use of ami- line hydrochloride, 4 ml, at concentrations of 5, 10, and 20 mM triptyline for nerve blockade in humans. When a new group) was used for each volunteer. If no major side drug or new indication for an already approved drug is/9–4 ؍ n) effects and nerve block were encountered, comparison in a tested clinically, the United States Food and Drug Admin- randomized, double-blinded trial of amitriptyline (20 mM)to group), was to follow. istration mandates a phase Ia trial (which is designed to/9–4 ؍placebo and bupivacaine (4 mM)(n A blunt needle was used to grade the pain, and motor blockade detect adverse effects) followed by a phase Ib trial (de- was assessed by the Froment test. signed to compare the new treatment against placebo, Results: There was no significant statistical difference in standard drugs, or both) in healthy volunteers.14–16 Our terms of side effects (pain, swelling, erythema, and sedation) goal was to conduct a phase Ia study to evaluate the side among any groups. The analgesic effects of 20 mM amitriptyline and4mM bupivacaine solution were significantly higher than effect profile of amitriptyline when used as a local anes- those of the placebo solution. thetic for peripheral nerve blockade in the usual dose Conclusions: Because of the lack of evidence that amitripty- escalating fashion. If any severe side effect was present, line provides better nerve blockade than current local anesthet- the study was to be halted immediately. If it seemed that ics and the potential for neurotoxicity, its use for peripheral the side effect profile of amitriptyline was similar to that nerve blockade in humans seems limited. seen with currently available local anesthetics and clear signs of nerve blocking capabilities were present, a THE antidepressant amitriptyline is used as an adjuvant phase Ib study to evaluate the efficacy of this drug in in the treatment of a variety of chronic pain conditions.1 comparison with bupivacaine and placebo was to Inhibition of norepinephrine and serotonin reuptake2 follow. are only one of its many potential mechanisms of action. ␣ There is also evidence that amitriptyline blocks 2-adren- Preclinical Safety Data 3 4 5 ergic, nicotinic, muscarinic cholinergic, N-methyl-D- Safety must be the most important consideration in the 6 7 aspartate, and histaminergic receptors and interacts clinical investigation of new drugs or indications.17 Car- diac toxicity and neurotoxicity are the major concerns for local anesthetics and are therefore the most impor- * Attending Anesthesiologist, Trauma Hospital Lorenz Boehler. † Assistant tant to consider before embarking on a clinical trial. In Professor, # Associate Professor, ʈ Research Assistant, Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, § Instructor, rats, intravenous amitriptyline administration has been Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital found to be less cardiotoxic than bupivacaine as a bolus and Harvard Medical School, Boston, Massachusetts. ‡ Professor, Institute of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria. injection (simulating accidental intravascular injection Received from the Trauma Hospital Lorenz Boehler, Vienna, Austria, and the during regional anesthesia). Also, cardiac toxicity has not Pain Research Center, Department of Anesthesiology, Perioperative and Pain appeared as a major concern in the decades of intrave- Medicine, Brigham and Women’s Hospital, Boston, Massachusetts. Submitted for 18 publication November 12, 2003. Accepted for publication February 5, 2004. nous use in Europe in much higher dosages. Supported by research grant Nos. GM48090 (to Dr. Wang) and GM64051 (to Dr. We conducted a number of pilot studies with repeat Gerner) from the National Institutes of Health, Bethesda, Maryland. Patent infor- mation: Wang GK, Gerner P, inventors. The Brigham and Women’s Hospital, Inc., percutaneous injections of amitriptyline for rat sciatic assignee. Tricyclic antidepressants and their analogues as long acting local anes- nerve blockade at high dosages (0.2 ml amitriptyline, thetics and analgesics. U.S. Patent 60/235 432. April 8, 2003. M ϭ Address reprint requests to Dr. Gerner: Department of Anesthesiology, Peri- 40 m , every day for 3 days; n 6) to preliminarily operative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis Street, evaluate direct neurotoxicity. Neurobehavioral examina- Boston, Massachusetts 02115. Address electronic mail to: [email protected]. Individual article reprints may be purchased through the Journal Web site, tion (response to pinch of the fifth toe and motor www.anesthesiology.org. strength) seemed to have returned to baseline after sev- Anesthesiology, V 100, No 6, Jun 2004 1511 1512 FRIDRICH ET AL. eral days. Then, the animals were euthanized, and the nent and irreversible nerve damage was a possibility and sciatic nerves were excised. After fixation, cross-sections were again made aware of that possibility immediately of the sciatic nerve were taken, embedded in paraffin, before the procedure. and stained with hematoxylin and eosin. None of these The phase Ia safety assessment study was conducted rats revealed histopathologically detectable nerve dam- using a dose-escalating, open-label style. Initially, only age. Therefore, we concluded that a human trial was subjects for the phase Ia study were enrolled for the justified. However, this percutaneous approach does not 5mM (n ϭ 9) concentration. Only in the absence of guarantee that the drug is actually applied in close prox- predefined significant side effects was the study to pro- imity to the nerve. The limitations of this approach are ceed to a doubled concentration of 10 mM (n ϭ 9) and presented in detail in the Discussion section. finally to 20 mM (n ϭ 4). The phase Ib efficacy assess- ment study was randomized (by a computer-generated Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/100/6/1511/356212/0000542-200406000-00025.pdf by guest on 27 September 2021 list) and double blinded. All phase Ib subjects including the bupivacaine and the normal saline group were also Materials and Methods evaluated for side effects to compare the incidence and severity of side effects. Written approval for the use of human subjects was obtained from the local Human Research Committee of Drugs the Trauma Hospital Lorenz Boehler, Vienna, Austria. Amitriptyline hydrochloride (Saroten®, 50 mg/2 ml; Financial compensation was offered for participation. Lundbeck Inc., Copenhagen Valby, Denmark) was di- luted with sodium chloride (0.9%) and adjusted to pH Inclusion Criteria 6.0–6.2 with sodium bicarbonate by an experienced Inclusion criteria were as follows: pharmacist under strict sterile conditions. Each subject received 4 ml of one of the following solutions: 5, 10, or 1. Healthy men and women between the ages of 19 20 mM amitriptyline in vehicle—resulting in a total dose and 65. of 6.3, 12.6, or 25.2 mg amitriptyline, respectively, 4 mM 2. A negative pregnancy examination within 24 h of (0.125%, 5.0 mg) bupivacaine or normal saline. study for female subjects. (A pregnancy test is de- ferred if the female subject is not of childbearing Ulnar Nerve Block potential [defined as postmenopausal for at least 1 yr] This procedure was performed by an anesthesiologist or is surgically sterile [bilateral tubal ligation, bilateral experienced in this technique, as previously de- oophorectomy, or hysterectomy]. If subject is of scribed.19 In brief, the area of the left wrist was disin- childbearing potential, she was categorized as not fected with Betadine (Purdue Pharma, Stamford, CT), pregnant if confirmed by negative serum pregnancy and a 25-gauge needle was inserted on the medial side of test at time of screening.) the ulnar artery and advanced between it and the flexor 3. Subject has voluntarily signed and dated an informed carpi ulnaris to the level of the ulnar styloid. The left side consent form. was used, as all subjects were right handed. When a par- esthesia was elicited, the needle was retracted 1–2mm, Exclusion Criteria and, after a negative test result for aspiration of blood was Exclusion criteria were as follows: obtained, 4 ml test solution was injected. 1. Subjects with dermatologic conditions in the area of Evaluation of Side Effects application.
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