COVER STORY:From biological weapon to medical therapy

2009/11/24

ANNIE FREEDA CRUEZ and SANTHA OORJITHAM

Botulinum neurotoxin, better known here as the Botox or Dysport brands, is now accepted as a therapy for neurological problems. But the experts warn ANNIE FREEDA CRUEZ and SANTHA OORJITHAM that it is a poison which must be handled with care. AT first, we only knew that it caused a severe, sometimes fatal, form of food poisoning — which is now prevented by better food technology and hygiene.

By World War II, a young US army officer, Dr Edward Schantz, was preparing huge amounts of botulinum neurotoxin (BoNT) at Fort Detrick and according to some reports, the plan was for prostitutes to assassinate Japanese officers with capsules containing a lethal dose.

But the US dropped biological weapons in the 1960s and Dr Schantz began testing BoNT on monkeys as a treatment for crossed eyes (strabismus).

In 1989, the US Food and Drug Administration (FDA) approved it as a drug to treat crossed eyes, eye spasms (blepharospasm) and hemifacial spasms (involuntary contractions on one side of the face).

In 2000, the FDA approved it for treatment of cervical dystonia — abnormal tightening and twisting of head and neck muscles.

And in 2002, it also approved BoNT for cosmetic treatment of wrinkles at the brow line. Here in Malaysia, BoNT is registered as a prescription medicine. It can only be injected by registered medical practitioners and not by untrained professionals, Director-General of Health Tan Sri Dr Ismail Merican stressed.

And these doctors must strictly follow the “product insert” which spells out how it must be used and for which medical conditions. Its safe and effective use “depends upon proper storage of the product, selection of the correct dose and proper reconstitution and administration techniques,” he added.

“Any practitioner who uses it for a condition other than what has been approved is using it in an ‘off label’ way and can be held responsible for any untoward reaction which may happen to the patient, if it can be shown to be due to the use of the product,” the Director-General warned.

BoNT can be used for temporary treatment of wrinkles between and above the eyebrows but it is not a cosmetic product, he explained. Under the Control of Drugs and Cosmetic (Amendment) Regulations 2007, cosmetic products are for external use only.

Beauty centres can only offer BoNT injections if they are prescribed and administered by doctors, Dr Ismail said, adding that all this would be addressed in the Cosmetology Bill which the Ministry hopes will be tabled in Parliament by next year.

BoNT is a harmful toxin that affects the nervous system. It enters the nerve cell and blocks release of acetylcholine, the neurotransmitter that carries messages to muscle cells, other nerve cells or glands.

“It is a very effective drug to achieve temporary paralysis of the muscles when they are overactive,” said Associate Professor Dr Norlinah Mohamed Ibrahim, head of Universiti Kebangsaan Medical Centre's neurology unit.

She prescribes it for dystonia (muscle contractions) such as eye or facial spasms and spasticity — overactive muscles due to stroke, cerebral palsy, traumatic brain or spinal cord injury or multiple sclerosis.

“It does not just cause paralysis at the neuromuscular junction (where the nerve ending comes into contact with a muscle fibre) but also blocks chemicals involved in pain perception,” she added. So it can provide pain relief to chronic migraine and tension-type headaches as well as chronic muscular pain syndrome such as fibromyalgia and chronic back pain.

But she only gives injections to patients with moderate to severe disabling which affects their quality of life. She starts with the lowest dose and increases it gradually: “There is no antidote once given, so we have to be careful especially not to inject it into a blood vessel, to prevent BoNT getting into the circulation.” She also warns them of the side effects. “Usually there are no side effects if the correct dose is given to the appropriate muscle,” she said.

But an excessive dose can cause excessive paralysis of the targeted muscles or other muscles within the injection area. For example, an injection around the eye muscle for eye spasms could cause the eyelid to become weak: “Patients may complain of temporary eyelid droop or even facial droop.” Other side effects include irritation such as redness, bruising, dry eyes, dry mouth, swallowing problems and blurred vision. And since the product contains albumin, a derivative of human blood, there is an extremely remote risk (thanks to donor screening and effective manufacturing processes) of transmission of viral diseases, Dr Ismail noted.

The Malaysian Adverse Drug Reactions Advisory Committee has received five complaints of adverse drug reactions to BoNT injections for medical conditions, he said. One patient with cerebral palsy reported breathing difficulty while the others had injection site reactions, including pain and redness. No formal complaints of death due to BoNT injections have been made here, but the World Health Organisation reports 22 deaths since 1992.

The former head of Hospital Kuala Lumpur’s neurology unit, Datuk Dr Raihanah Abdul Khalid, said training hospitals have a very structured programme. At HKL, juniors were only allowed to administer BoNT under supervision in their second year and by themselves after three years.

“We do not give it more than once in three months,” she added, “otherwise the patient might develop antibodies and resistance. Then it would not work.” Now a consultant neurologist to Pantai Medical Centre, Assunta Hospital and Tawakal Hospital, she said that severe allergic reactions are very rare, but hospitals have whatever is needed on hand. If BoNT is administered in a clinic, she said, it should have oxygen masks and intubation facilities. In 2006, the National Fatwa Council ruled that Muslims were forbidden to use BoNT for cosmetic purposes, although it could be used for medical conditions.

Dr Norlinah is against the use of BoNT for cosmetic purposes. “It’s a potentially dangerous drug, especially if used incorrectly by inexperienced people,” she warned. “It is not an anti-ageing drug. It causes muscle paralysis and there may be side effects if it is injected at the wrong site. It may result in facial asymmetry causing more disfigurement to the patients.” But for patients with neurological problems, she said it is a very important medicine. “There is very little we can do for dystonia without it, apart from brain surgery, which is expensive and selective.” Her only complaint is the cost — between RM1,000 and RM1,500 per vial. While a vial can be used for up to 30 people for cosmetic patients, one of her patients may need a whole vial.

UKM Medical Centre partially funds the treatment so that patients only pay a minimal flat rate for injections. But she hopes the price can be fixed at the national level “so that there is no exploitation”.

Still, almost all her patients who are given a BoNT injection for dystonia and spasms return for repeat injections, she noted: “Some patients with dystonia improve after only one injection. It actually changes their life.” Dr Ismail says only medical practitioners are allowed to prescribe and inject botulinum neurotoxin.

Botox and Dysport are two brands of botulinum neurotoxin, now used for movement disorders. Botulinum neurotoxin injections are used to cure spasms and over-active muscles. — Picture posed by model. Dr Norlinah says botulinum neurotoxin temporarily paralyses over-active muscles.

To inject or not to inject?

DOCTORS agree on the use of botulinum neurotoxin (BoNT) for movement disorders. But the reaction to its use to treat wrinkles has been mixed, especially among the entertainment community.
Since it temporarily weakens or paralyses muscles, it can cause eyelid droop or facial droop. “That is why more than one actor has stopped receiving BoNT injections,” said a local medical expert.
Torchwood star John Barrowman admitted to Britain’s New! magazine last year that he regularly has Botox (one brand of BoNT) injections to smooth out wrinkles.

“I don’t swear by it, but I’ve tried it and I think it’s quite good,” said the 42-year-old judge in BBC’s talent show I’d Do Anything.
“I can still smile and look expressive.”
On the other hand, 38-year-old actress Amanda Holden told News of the World that although she had Botox injections in the past, she had stopped for fear it might affect her facial expressions.
“I need my muscles to move,” said the judge of Britain’s Got Talent. “As an actress, Botox is a bit of a stupid thing to do because you need a moveable face. But my frown is back so it’s definitely something I'll consider again.”
Earlier this year, Agora star Rachel Weisz called for an onscreen ban on BoNT injections.
“It should be banned for actors, as steroids are for sportsmen,” she told Harper’s Bazaar. “Acting is all about expression; why would you want to iron out a frown?”
And the injections have cost at least one actor a role. London-based casting director Jeremy Zimmerman told The Observer a few years ago that he had vetoed Mickey Rourke for the leading role in a British film he was working on at the time.
“I had to explain to his agent that we wouldn’t be using him because his face looks so frozen after his recent operations,” he said.
“It’s a shame because he would have been perfect for the part but he just looks so strange now, so expressionless.”