HISTORY

Naltrexone was synthesized in the 1960s and first used clinically in the early 1970s. It soon became evident that its therapeutic potential was undermined by poor compliance and the first studies of depot preparations date from the mid 70s. Human studies were done in the early1980s and most of the basic science was known by then.

Naltrexone is a pure narcotic antagonist with a low oral bioavailability around 40% Clinical data has indicated that poor medication compliance occurs with daily oral naltrexone maintenance treatment for opioid dependence. Naltrexone’s lack of agonist activity causes no withdrawal negative consequences without its administration.  Better naltrexone compliance has been observed when a responsible adult is available to supervise daily naltrexone dosing.  It is reported that the method of daily oral naltrexone maintenance is not appropriate. Masters proposes that long-term sustained delivery of naltrexone would be more appropriate in the treatment of drug addiction.  Wise (1984) developed a naltrexone (70%)-poly(D,L-lactide-co-glycolide) copolymer (30%) which was the first biodegradable drug delivery system approved by the Food and Drug Administration (FDA) for clinical testing, and was limited by “burst release” in human trials.  Previous findings also suggested that polymeric naltrexone sustained release systems are biocompatible formulations.

FORMULATION AND CLINICAL EXPERIENCE

The first implants for clinical as opposed to experimental use were made around 1997 by George Malmberg of Wedgewood Pharmacy, Sewell, NJ. These ‘first generation’ models currently consist of a cigarette-butt size pellet of  compressed naltrexone powder with a small percentage of magnesium stearate, which is apparently a normal component of implants but sometimes causes tissue irritation.  At one time, they also contained 10mg of slow-release triamcinolone to reduce tissue reactions. These implants dissolve and disappear completely in about  5-7 weeks on average. A similar implant has been made for internal use by the pharmacy of a Berlin hospital. It has no stearate component and seems to have better tissue tolerability and will be available by the end of 2006. The later implant is manufactured by George Sherman at Towne Pharmacy, NJ and  is a 1g  pellet with 10mg of slow release triamcinolone. It is manufactured in a novel manner producing effective opioid blockage for 12 to 14 weeks. The same product is now licensed in Russia as Prodetoxone and is currently being used are three extensive trials being conducted at St.Petersburg Scientific-Research Center of Addictions and Psychopharmacology, Pavlov Medical University,
St.Petersburg,Russia in conjunction with the University of Pennsylvania, Department of Psychiatry, Philadelphia, USA.

‘Second generation’ implants use another established implant technique - embedding naltrexone in a matrix of biodegradable polymer microspheres. The first available implant of this type is made by Dr George O’Neill of GO-Medical Industries in Perth, WA. The polymer takes 1-2 years to break down and naltrexone is released for 5-9 months or more, though opiate blockade may be only partial after about 4-7 months. They are generally well-tolerated and there is no need to include a steroid. Both types of implant are usually inserted with antibiotic prophylaxis and both can block very large amounts of heroin. Basic composition of the O’Neill implant is approximately 50% naltrexone, 49% of biodegradable polymer and £1% magnesium stearate.  The polymer material is similar material to that used in biodegradable sutures and screws and is an FDA approved substance. The polymer has been used previously in implantable norethisterone formulations (Beck et al, 1981). The incidence of foreign body reactions with polylactide biodegradable polymers has been recently reviewed (Perrin et al., 1997). Go Medical estimate an incidence of foreign body reaction of 4.9%, from accumulated data from 412 patients. Their is a several "new" second generation implants, the most recent is the LI LA naltrexone implant from China and is also based on the use of biodegradeable polymer, but the LI LA naltrexone implant appears to give good blood levels and hence effective opiate blockage over 360 days. Then there are implants being developed by three American companies:

1. Addex naltrexone implants - Bartor Pharmacal Inc.

2. Trident naltrexone implants - Trident Inc.

3. Hydron naltrexone implants - Valera Pharma Inc.                  

the implants are at various stages of development.                                                          

With the exception of Prodetoxone none of the implants have a product licence even in their country of origin but they are made to appropriate pharmaceutical standards. All are sterilized by gamma irradiation or chemical sterlisation.

The polymer can also be formulated as a liquid vehicle for a depot injection of naltrexone. One Alkermes Inc. USA have been working on this for over 10 years.The product Vivitrol has been approved under special license by the FDA for use in the treatment of alcoholics. Other companies in various countries are working along similar lines.

TOXICITY

Since naltrexone is a relatively old drug, its properties are correspondingly well known. It appears to have no significant organ toxicity apart from very rare rashes. In particular, there are no reports of clinically significant liver toxicity.

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