Octreotide dependency and headache: a case report

A May, S Lederbogen1, HC Diener

Department of Neurology and the Department of Endocrinology1, University of Essen, Essen, Germany

Cephalalgia

May A, Lederbogen S, Diener HC. Octreotide dependency and headache: a case report. Cephalalgia1994;14:303-4. Oslo. ISSN 0333-1024

We report on headache induced by a somatostatin octapeptide analog (octreotide) used for the treatment ofacromegaly, This "rebound" headache has severe tension-type characteristics and occurs every 6-8 h. It resolvesdramatically within minutes with octreotide administration. This is the first report of headache developing undertreatment with octreotide. • Acromegaly, drug-induced headache, octreotide, tension headache

A May, Department of Neurology, University of Essen, Hufelandstrasse 55, 45147 Essen, Germany. Received 30November 1993, accepted 10 March 1994

Frequent or daily use of analgesics or specific headache medications may cause drug-induced headache. It isgenerally accepted that not only ergo-famine-containing drugs, but also other analgesics used for treatment ofmigraine or tension-type headache can lead to chronic headache (1). Chronic headache also occurs commonly inpatients with pituitary tumors. Headache is a prominent symptom in more than 50% of cases of acromegaly and ismore frequent than visual problems (18).

Extension of the tumor beyond the sella, causing sellar enlargement and thereby leading to mechanical pressureor traction on the meninges, is thought to be the cause of severe head pain. The cause of headache in somepeople with pituitary adenomas remains unclear, as the pain does not improve after surgery and seems to beunrelated to tumor size. Since the introduction of the long-acting somatostatin analog octreotide as treatment foracromegaly, there have been several reports of spontaneous, dramatic relief of chronic severe headache withoctreotide administration (4, 5). All authors have stressed that pain relief was dramatic, occurring within minutes ofthe dose, unrelated to decrease in tumor size or to suppression of growth hormone production.

We report a female patient with acromegaly treated with octreotide. She developed a typical drug-inducedheadache, which stopped only after withdrawal of octreotide.

Case report

A previously healthy 33-year-old woman presented in 1986 with clinical signs of acromegaly and growth hormonelevels were elevated. After surgery and radiotherapy the somatostatin analog octreotide was started for themanagement of her still active disease. The patient, who had no personal or family history of headache, developeda daily frontal, dull and pressing headache with no accompanying symptoms which increased with physical activity.The headache disappeared minutes after subcutaneous administration of octreotide. Pain relief occurred after eachand every dose of octreotide (50-100 mg/6 h) and did not occur in response to treatment with antirheumatic andantimigraine drugs. Despite gradually increasing doses of octreotide (to 700-800 mg/day) the headache occurredevery 4-6 h.

The patient developed cholelithiasis, a common complication of octreotide therapy, and the growth hormonelevel normalized. She was unable, however, to stop the hormonal treatment of the severe, recurrent headache. Thepituitary adenoma showed no change in size on MRI and structural factors seemed, therefore, unlikely to beresponsible for the headache.

The patient was admitted to our clinic and octreotide was stopped. The headache markedly worsened and wastreated with regular doses of oral naproxen, metamizol, and intravenous acetylsalicylic acid. Within 2-3 days, theheadache pain improved and the medications were tapered over weeks and stopped. She left the clinic pain-freewithout medication.

Discussion

The analgesic effect of somatostatin was reported 10 years ago (5-7). The mechanism of analgesia ofsomatostatin is unknown. It has been postulated that the analgesic effect may be due to a central mechanism at thelevel of pain-modulating structures, perhaps in combination with a general positive behavioral activation (2). Thishypothesis is supported by three findings: (i) Rubinov et al. showed that CSF somatostatin was significantlydecreased in depressed patients compared with normal volunteers (8). (ii) Intraventricular injection of somatostatin

increases cortical excitability and produces arousal in rabbits (9). (iii) Serby et al. found a lower somatostatin level in dementias such asAlzheimer's disease (10). A direct effect of somatostatin on opioid receptors has also been considered (11). Somatostatin and its analog,octreotide, have since been shown to be highly selective opioid antagonists (12, 13). Moreover, clinical studies have shown that naloxonedoes not prevent somatostatin-induced analgesia (4).

The theory that octreotide induces analgesia via inhibition of the release of unknown algogenic peptides (e.g. substance P) by the tumor, incombination with activation of endogenous analgesic peptides (e.g. endorphins) (4, 5, 7), is of great interest. Hypothetically, the release ofalgogenic substances causes facial and head pain by acting upon the pain-promoting fibers of the trigeminal system. Octreotide providesanalgesia in cluster headache (11), which theoretically involves the trigeminal system (14, 19), and in carcinoid syndrome, where tachykininssuch as substance P are known to be increased (15). Furthermore, Vecsei et al. found a relationship between decreased levels of serumsomatostatin and the occurrence of migraine (21).

In an animal model, the intravenous administration of serotonin agonists and octreotide blocked plasma extravasation induced by unilateralelectrical trigeminal ganglion stimulation (16). Neurogenically induced extravasation in the microcirculation of the dura mater may cause amigraine and cluster headache (20). Perivascular inflammation was blocked by octreotide if extravasation of plasma followed either unilateralelectrical trigeminal ganglion stimulation or capsaicin administration, but not if it was mediated directly by the neuropeptide substance P.Octreotide most likely has an effect by blocking release of inflammation promoting substance P from trigeminal nerve endings without directlyinfluencing substance P (16). This case supports our theory that increasing octreotide doses cause up-regulation of substance P receptors,accounting for the analgesic effect of this somatostatin analog and the occurrence of headache on its withdrawal.

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