Its Analgesic Action on Cluster Headache

Endocrine Journal 2004, 51 (5), 449–452

Long-term Effects of Octreotide on Pituitary Gigantism: Its Analgesic Action on Cluster Headache

FUMIO OTSUKA, SATOSHI MIZOBUCHI*, TOSHIO OGURA, KENJI SATO*, MASATAKA YOKOYAMA* AND HIROFUMI MAKINO

Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama 700- 8558, Japan *Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700- 8558, Japan

Abstract. We report the case of 19-year-old man with pituitary gigantism due to growth hormone-producing pituitary macroadenoma. The patient complained of recurrent headache and excessive growth spurt since age 15. Octreotide administration was initiated following transsphenoidal pituitary adenomectomy. Octreotide injection for 4 years efficaciously reduced the size of remnant adenoma as well as serum growth hormone levels. Notably, octreotide exhibited a potent analgesic effect on his intractable cluster headache that has continued even after reduction of the adenoma volume. The analgesic effect lasted 2 to 6 hours after each injection and no tachyphylaxis to octreotide appeared during 4-year treatment. To characterize the headache and the pain intensity, analgesic drugs including octreotide, lidocaine, morphine and thiopental were tested using a visual analogue scale (VAS) evaluation, with the result that octreotide exhibited a prompt and complete disappearance of the headache. Headache relief was in part reproduced by morphine injection (56% reduction) but not by lidocaine or thiopental. The present case suggests that the intractable headache associated with pituitary gigantism is possibly related to the endogenous opioid system. Thus, the headache control by octreotide is clinically helpful for continuation of the self-injection regimen.

Key words: Headache, Octreotide, Opioid receptor, Pituitary gigantism, Visual analogue scale (Endocrine Journal 51: 449–452, 2004)

THE beneficial effects of octreotide are recognized in Case Presentation acromegaly caused by pituitary adenomas [1]. How- ever, the long-term effect of octreotide has not been A 19-year-old Japanese man who complained of well documented in pituitary gigantism because of its recurrent headache, prolonged growth spurt and in- extremely rare incidence compared with acromegaly creases in foot length and body weight was consulted. [2]. We here present a therapeutic experience regard- His growth velocity had become remarkable since age ing pituitary gigantism, which was treated with octreo- 15. His height was 164 cm (+1 SD), 178 cm (+2 SD), tide injection for four years after transshpenoidal 186 cm (>+2 SD), 194 cm (>+2 SD) at 13, 15, 16, and surgery. In the present report, we specifically evalu- 18 years old (relative to the Japanese growth chart), ated the analgesic effect of octreotide regarding the respectively. On admission, he was 208 cm tall, chronic headache associated with pituitary gigantism. 115.6 kg body weight (body mass index, 27.6 kg/m2) and 33 cm of foot size. Acromegaloid features includ- ed bulging forehead and jaw, with little enlargement of nose and tongue, although radiological examination Received: April 16, 2004 disclosed mild acromegalic changes of finger tip and Accepted: June 28, 2004 Correspondence to: Fumio OTSUKA, M.D., Ph.D., Department heel pad thickness. Cranial magnetic resonance of Medicine and Clinical Science, Okayama University Graduate imaging (MRI) revealed a pituitary tumor partially School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama enhanced by gadolinium, occupying the sellar region 700-8558, Japan with extension to optic chiasm and right cavernous 450 OTSUKA et al.

Fig. 1. Changes of pituitary MRI finding and serum levels of GH and IGF-1. Octreotide injection significantly diminished the remnant pituitary adenoma after transsphenoidal surgery (TSS) (arrows; upper panel) and serum levels of GH and IGF-1 were gradually decreased after 4-year continuation of octreotide (lower panel). sinus (Fig. 1, upper panel). Serum growth hormone relieved by octreotide injection but hardly reduced by (GH) and insulin-like growth factor (IGF)-1 levels common painkillers including anti-inflammatory and were markedly elevated (96.5 ng/ml and 1064.7 ng/ml; antimigraine drugs. After subcutaneous injection of normal, 0.1–2.9 and 219–509, respectively). GH octreotide (25 to 50 g), his headache was ameliorated levels were paradoxically increased (~1.5 fold) in immediately within a few minutes, with the effects response to thyrotropin releasing hormone and not lasting for 2 to 6 hours after each injection. Successful suppressed by glucose. The pituitary tumor partially treatment with octreotide was also shown in the resected by transsphenoidal surgery (TSS) was histo- metabolic normalization including glucose tolerance logically diagnosed as pituitary adenoma. After sur- and serum lipid level. While his height and features gery the basal levels of GH were decreased by about remain almost unchanged, his body weight gain has 60%, but both GH and IGF-1 levels remained elevated stopped. There were no apparent side effects of at about 20 ng/ml and 1000 ng/ml, respectively (Fig. 1, octreotide including major gastrointestinal trouble and lower panel). In an attempt to reduce the GH levels, gallstones throughout the therapy. octreotide injection was begun immediately and the self-injection (300 g/day) has been continued every Drug provocation test day. After 4-year treatment with octreotide injection, the residual adenoma was markedly diminished and In order to clarify the effectiveness of analgesic the basal GH level became lowered to ~2 ng/ml (see agents on the patient’s chronic headache, drug chal- Fig. 1). However, his cluster headache occurred even lenge tests were performed after obtaining informed after adequate reduction of the volume of pituitary consent. When the patient complained of severe head- adenoma. His headache exhibited pulsatile pain and ache, the analgesic effect of octreotide (25 g s.c.), attacked him almost every morning; it lasted for 2 to lidocaine (50 mg i.v.), morphine (3 mg i.v.) and thio- 3 hours accompanied by occasional rhinorrhea or pental (50–75 mg i.v.) was evaluated at our outpatient lacrimation. It was intriguing that the headache was clinic. Each drug was administered following placebo GIGANTISM TREATED WITH OCTREOTIDE 451

regimen was the alleviative effect of octreotide on his headache that had been resistant to common painkill- ers. As reported in several cases of acromegaly [4–8], octreotide injection showed a potent and rapid effect that enabled our patient to reduce the magnitude of the cluster-like headache in a few minutes after injection. The headache shown in acromegaly patients was as- sociated with neither serum GH levels nor tumor size of pituitary adenoma as reported by Pascual et al. [9]. In the present case, the prompt and potent analgesic effect induced by octreotide was not mimicked by a sodium channel blocker lidocaine, which only margin- ally decreased the VAS of headache. Thiopental, a barbiturate, showed no effect on the VAS score in the Fig. 2. Effects of analgesic drugs on the VAS score of head- present test, suggesting that the headache is not simply ache. Octreotide (25 g s.c.), lidocaine (50 mg i.v.), a psychogenic reaction. Thus, the characteristic of thiopental (50–75 mg i.v.) or morphine (3 mg i.v.) and/ headache is, at least in part, opioid-sensitive since or naloxone (0.2 mg) were administered following the the opioid-receptor agonist morphine significantly placebo (physiologic saline) injections. The pain evalu- reduced the VAS score, which was partially blocked ation using a 10-cm VAS method was performed before and 1 to 5 minutes after each administration. Data were by naloxone. shown as % changes of the VAS score. The analgesic mechanism of octreotide remains un- clear. Octreotide is shown to bind to opioid receptors in vitro with a high affinity, by which octreotide exerts (physiologic saline) injection and the pain intensity antagonistic properties to the opioids in animal studies was evaluated using a 10-cm visual analogue scale [10]. On the contrary, Pascual and colleagues reported (VAS) [3] before and 1 or 5 minutes after each injec- that the analgesic effect of octreotide was not influ- tion. When the analgesic effect was incomplete, addi- enced by the morphine antagonist naloxone, suggest- tive drug injections were subsequently performed and ing that mechanisms other than the opioid system may VAS was evaluated at 1 or 5 minutes after each injec- be involved in the analgesic effect of octreotide [9]. tion. In case of the morphine test, a morphine antago- As the involvement of opioid receptor in the octreotide nist, naloxone (0.2 mg i.v.), was administered after a actions is controversial, future studies are necessary to series of morphine injections and the changes in VAS elucidate the analgesic mechanism of octreotide in was reevaluated. As shown in Fig. 2, octreotide exhib- patients with acromegaly/gigantism, which would lead ited a remarkable analgesic effect and it completely to clarifying the underlying mechanism of the intrac- suppressed the headache within 5 minutes. Lidocaine table headache due to pituitary disorders. showed an unstable and slow effect with at most It is possible that our patient could have developed 40% reduction of the VAS score. Morphine rapidly octreotide dependency [11–13] regarding headache reduced the VAS score to 56% of the placebo level, during the therapy. However, we must note that which was partially abolished by a subsequent admin- tachyphylaxis to octreotide did not emerge and that istration of naloxone. Thiopental had no analgesic almost the same dose of octreotide has been effective effect on his headache. to relieve the headache during the 4-year observa- tion period, while the occurrence of octreotide tachy- phylaxis on GH reduction has only rarely been reported Discussion in acromegaly [14–16]. Our present case hence shows the effectiveness of long-term treatment with Acromegaly/gigantism patients in general have octreotide on pituitary gigantism including GH reduc- some difficulties in handling the injections, resulting tion and tumor diminution as well as on headache in its discontinuation. Nonetheless, a key factor that control, the latter of which is highly likely to contribute helped the present case to continue the self-injection to continuation of the self-injection regimen. 452 OTSUKA et al.

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