Octreotide
SMS 201-995, Octreotide acetate, Octreotide LAR, Octreotide long-acting release, Octreotide depot
Octreotide is a synthetic eight-amino-acid analogue of the natural hormone somatostatin, engineered to resist the enzymes that destroy the parent peptide within minutes. It has been a licensed medicine since 1988 and is used to control acromegaly, the flushing and diarrhoea of carcinoid syndrome, and hormone oversecretion from neuroendocrine tumours. It also slows tumour growth in certain midgut neuroendocrine tumours.
Mechanism
Octreotide is an agonist at the G-protein-coupled somatostatin receptor family, with high affinity for SSTR2, moderate affinity for SSTR5 and SSTR3, and essentially no meaningful binding at SSTR1 or SSTR4. This narrow profile is the whole point of the molecule: native somatostatin hits all five subtypes indiscriminately, whereas SSTR2 is the subtype most densely expressed on growth-hormone-secreting pituitary adenomas and on well-differentiated gastroenteropancreatic neuroendocrine tumours. Receptor occupancy couples through Gi/Go proteins to inhibit adenylyl cyclase, open inwardly rectifying potassium channels and close voltage-gated calcium channels. The resulting membrane hyperpolarisation and fall in intracellular calcium shut down regulated exocytosis, which is why a single drug can simultaneously suppress growth hormone, insulin, glucagon, gastrin, vasoactive intestinal peptide, serotonin, secretin, motilin and pancreatic polypeptide.
The antiproliferative effect is a separate mechanism from the antisecretory one. In preclinical work, SSTR2 and SSTR3 recruit the protein tyrosine phosphatases SHP-1 and SHP-2, which dephosphorylate growth factor receptors and drive cell-cycle arrest through p27kip1; SSTR3 signalling has additionally been reported to trigger p53-dependent apoptosis in cell models. These pathways are the proposed pharmacological basis for the progression-free survival benefit seen in neuroendocrine tumour trials, though the trials themselves measured tumour progression rather than the pathway. A third, quite different action underlies its use in variceal haemorrhage: octreotide causes splanchnic vasoconstriction and reduces portal venous inflow, partly by inhibiting the release of vasodilatory gut peptides such as glucagon. The structural modifications that make all this practical are the D-amino acids at positions 1 and 4, the shortened cyclic core and the C-terminal threoninol, which together block the aminopeptidase and endopeptidase cleavage that gives native somatostatin its two-minute lifespan.
What the research shows
The therapeutic case for octreotide rests on three separate literatures. In acromegaly, roughly 55-65% of unselected patients achieve a normal IGF-I on a long-acting somatostatin analogue, with better rates in those whose tumours express SSTR2 densely and are densely granulated on histology; the Chanson figure of 65% after switching is representative, though that study was a switch design rather than a parallel comparison. In carcinoid syndrome, symptomatic response rates of roughly 58-71% have been reproduced consistently from Kvols in 1986 through the 1999 formulation trial. In neuroendocrine tumour biology, PROMID established a genuine antiproliferative effect on time to tumour progression in 85 patients, though it was not powered for overall survival and the later survival analysis did not demonstrate a significant survival gain, plausibly because most placebo patients crossed over on progression.
The honest counterweights matter. The Cochrane review of somatostatin analogues in acute variceal bleeding found no mortality benefit across 21 trials and 2,588 patients and doubted whether the transfusion sparing is worthwhile, although it did find a significant reduction in failure of initial haemostasis. Response in acromegaly is not universal: a substantial minority of patients are resistant, and switching between first-generation analogues rarely rescues them. Tachyphylaxis in carcinoid syndrome is commonly described over years, requiring dose escalation. And in insulinoma, octreotide can paradoxically worsen hypoglycaemia when the tumour lacks SSTR2, because counter-regulatory glucagon and growth hormone are suppressed more than insulin.
Evidence assessment
High-quality evidence
Octreotide has been continuously licensed in major markets since 1988, with regulator-approved labelling in the United States, United Kingdom and European Union. The evidence base includes a randomised placebo-controlled trial with a hard endpoint (PROMID, time to tumour progression, 85 patients), randomised formulation-comparison trials in carcinoid syndrome and acromegaly, and nearly four decades of post-marketing pharmacovigilance. This is genuinely strong evidence for the licensed indications. It is not uniformly strong across every use: the Cochrane evidence in acute variceal bleeding is negative for mortality, and that indication is carried on weaker ground than the endocrine ones.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue Preclinical only
Flushing and diarrhoea were promptly relieved in 22 of 25 patients, and 18 of 25 (72%) had a fall of 50% or more in urinary 5-hydroxyindoleacetic acid. Median duration of biochemical response was more than 12 months (range 1 to more than 18) with no serious toxicity observed. This is the study that established somatostatin analogues as symptomatic therapy for carcinoid syndrome, but it had no control group and response was judged against pretreatment values only.
Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome Preclinical only
Complete or partial treatment success was comparable across all four arms: 58.3% subcutaneous, 66.7% at 10 mg, 71.4% at 20 mg and 61.9% at 30 mg, with P at or above 0.72 for every pairwise comparison. The authors concluded that once steady state is reached the depot controls symptoms at least as well as thrice-daily injections, and recommended a 20 mg starting dose with supplemental subcutaneous cover for roughly the first two weeks.
Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group Preclinical only
Median time to tumour progression was 14.3 months with octreotide LAR versus 6.0 months with placebo (hazard ratio 0.34). Benefit was seen in both functionally active and inactive tumours. This was the first placebo-controlled demonstration that a somatostatin analogue is antiproliferative and not merely antisecretory. The trial was not powered for overall survival, and objective tumour responses were rare in both arms.
Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly Preclinical only
Mean growth hormone fell from 9.6 to 6.8 mU/l after the switch. The proportion with GH at or below 2.6 mU/l rose from 14% to 35%, and the proportion with a normal IGF-I rose from 48% to 65% (all P<0.001). Note the ceiling: even after optimisation roughly a third of patients remained biochemically uncontrolled. Note also the design limitation, corrected during audit: this is a within-patient switch study with randomised switch timing, not a parallel-group head-to-head trial, so the apparent superiority of octreotide LAR is confounded by order and by the older comparator formulation.
Somatostatin analogues for acute bleeding oesophageal varices Preclinical only
A deliberately included largely negative result. Mortality was not significantly reduced (relative risk 0.97, 95% CI 0.75 to 1.25 in trials at low risk of bias). Blood transfused was 0.7 units less in the low-risk-of-bias trials, which the reviewers summarised as about half a unit saved per patient and doubted was worthwhile. Failure of initial haemostasis was significantly reduced (RR 0.68, 0.54 to 0.87), a point of genuine benefit the draft had omitted. Rebleeding was not significantly reduced in the low-risk-of-bias trials (RR 0.84, 0.52 to 1.37) although it was in the weaker trials (RR 0.36).
Safety
The most characteristic long-term problem is gallbladder disease. Octreotide inhibits cholecystokinin release and gallbladder contractility, and biliary sludge or gallstones develop in a large minority of patients on prolonged therapy, sometimes cited at up to 50%, though most remain asymptomatic. Gastrointestinal effects dominate early treatment: abdominal cramping, bloating, nausea, loose stools and steatorrhoea from suppressed pancreatic exocrine secretion, usually settling over weeks. Fat malabsorption can produce fat-soluble vitamin deficiency and vitamin B12 deficiency with long use.
Glycaemic effects are bidirectional and require monitoring, because insulin, glucagon and growth hormone are all suppressed: some patients with acromegaly see glucose improve as growth-hormone-driven insulin resistance falls, while others become hyperglycaemic. Sinus bradycardia and conduction changes occur, relevant in patients on beta-blockers or with pre-existing cardiac disease. Injection-site pain and induration are common. Hypothyroidism from suppressed thyrotropin, and pancreatitis, are uncommon. Abrupt withdrawal in carcinoid syndrome can precipitate severe symptom rebound. Octreotide is not appropriate for self-directed use; it is a specialist-initiated medicine requiring biochemical and gallbladder monitoring.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Licensed by the MHRA. Indications differ by formulation. The immediate-release subcutaneous injection covers acromegaly, symptomatic control of functioning gastroenteropancreatic neuroendocrine tumours, prevention of complications after pancreatic surgery, and emergency management of bleeding gastro-oesophageal varices in cirrhosis. The long-acting intramuscular depot covers acromegaly, functioning gastroenteropancreatic neuroendocrine tumours, control of tumour growth in advanced neuroendocrine tumours of the midgut or unknown primary where non-midgut origin has been excluded, and thyrotropin-secreting pituitary adenomas. Prescription-only medicine, initiated in specialist endocrine, oncology or hepatology settings. |
| United States | Approved by the FDA in 1988 as an immediate-release subcutaneous injection for acromegaly, for the severe diarrhoea and flushing of metastatic carcinoid tumours, and for the watery diarrhoea of VIPoma. The long-acting intramuscular depot was approved in 1998, and an oral delayed-release capsule for maintenance in acromegaly was approved in 2020. Multiple generics are available. Prescription-only. |
| WADA (sport) | Not prohibited on the current Prohibited List. Octreotide suppresses rather than stimulates growth hormone release, so it falls outside the S2.2 growth hormone secretagogue category, and it does not appear elsewhere on the List. The List is revised annually, and athletes should declare it as they should any prescribed medicine. |
Questions
Native somatostatin has a circulating half-life of one to three minutes, which makes it unusable outside a continuous infusion. Octreotide is a shortened eight-residue cyclic version carrying D-amino acids at two positions and a reduced C-terminal threoninol, all of which block peptidase attack and extend the half-life to around 90 minutes. It is also receptor-selective, targeting SSTR2 and SSTR5 rather than all five subtypes, which concentrates the effect on pituitary and neuroendocrine tumour cells.
Rarely. PROMID and comparable trials showed that octreotide delays progression rather than causing regression: objective tumour shrinkage was uncommon in both arms of PROMID. The clinical benefit is stabilisation of disease over months to years, which in indolent well-differentiated neuroendocrine tumours is a meaningful outcome in its own right, but it is not the same as shrinking a tumour.
Octreotide suppresses cholecystokinin, the hormone that triggers gallbladder emptying after a meal. Bile therefore stagnates in the gallbladder, concentrates and forms sludge, which can crystallise into stones. Most cases are silent and found only on surveillance ultrasound, but symptomatic biliary disease does occur, which is why ultrasound monitoring is part of standard long-term follow-up.
No. It does not appear on the current WADA Prohibited List. Because it suppresses growth hormone rather than stimulating it, it is pharmacologically the opposite of the growth hormone secretagogues in category S2.2. The List is revised annually, and athletes prescribed octreotide should still disclose it on doping control forms.