Archive for 05/02/2011


Los Angeles – Subkutane Implantate könnten die Compliance der Opiatabhängigen bei der Buprenorphin-Substitution verbessern und einen Schwarzmarkt verhindern. Eine Phase-III-Studie im US-amerikanischen Ärzteblatt JAMA 2010; 304: 1576-1583) attestiert dem Präparat eines US-Herstellers jetzt eine passable Wirksamkeit.

In der Substitutionstherapie von Heroinabhängigen ist Buprenorphin eine attraktive Alternative zu Methadon. Denn der partielle Opiat-Agonist ist weniger anfällig gegenüber Überdosierungen und auch außerhalb der großen Substitutionszentren verfügbar. In vielen Ländern ist die sublinguale Buprenorphin-Substitution deshalb sehr beliebt.

Es lässt sich allerdings kaum verhindern, dass das starke Opiat auf den Schwarzmarkt gelangt – selbst wenn es in vielen Ländern mit dem Antagonisten Naloxon versetzt ist. Bei einer unzuverlässigen Einnahme kommt es außerdem schnell zu Entzugssymptomen und die Rückfallquote der Patienten ist deshalb hoch.

Beide Probleme könnten durch subkutane Implantate gelöst werden, die den Wirkstoff über mehrere Monate kontrolliert freisetzen. Das Präparat eines US-Herstellers wurde jetzt an 18 Behandlungszentren des Landes in einer Phase-III-Studie untersucht.

108 Patienten – zu zwei Drittel Heroin-, zu einem Drittel Medikamentenabhängige – wurden jeweils vier 26 mm lange und 2,5 mm dicke Implantate in 2 bis 3 mm Tiefe ins Unterhautfettgewebe am Arm eingebracht.

Wenn notwendig konnten die Probanden ein fünftes Implantat erhalten. Nach 6 Monaten wurden alle Implantate entfernt, was einen kleinen chirurgischen Eingriff erfordert, der eine kurze Narbe hinterlässt. In einer Vergleichsgruppe von 55 Patienten wurden Implantate mit Placebo implantiert, was ethisch gerechtfertigt war, weil die Patienten in beiden Gruppen bei Bedarf zusätzlich Sublingualtabletten mit Buprenorphin erhalten konnten.

Wie Walter Ling von der Universität Los Angeles und Mitarbeiter berichten, erhöhten die Buprenorphin-Implantate den Anteil der negativen Urinkontrollen – als Hinweis auf einen fortgesetzten Drogenkonsum – von durchschnittlich 28,3 auf 40,4 Prozent.

Auch in den sekundären Endpunkten wurde eine Wirksamkeit nachgewiesen: Insgesamt 65,7 gegenüber 30,9 Prozent nahmen bis zum Schluss an der Studie teil. Auch die Häufigkeit von Entzugssymptomen wurde ebenfalls signifikant gesenkt.

Im Buprenorphin-Arm gab es keine Therapieversager: Alle kamen mit vier oder fünf Implantaten aus. Im Placebo-Arm wurden 30,9 Prozent der Patienten als Therapieversager eingestuft, weil sie häufiger als dreimal in der Woche Sublingualtabletten nachfragten.

Die Implantate lösten nur geringe Lokalreaktionen aus, wobei es zwischen Buprenorphin und Placebo keine Unterschiede gab. Der Hersteller führt derzeit eine zweite Phase-3-Studie durch und will sich nach deren Abschluss um eine Zulassung in den USA und in Europa bemühen. © rme/aerzteblatt.de

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ScienceDaily (Feb. 1, 2011) — Opiate abuse is a chronic disorder and maintaining abstinence represents a major challenge for addicts.

Individuals recovering from opiate dependence have long reported that while the acute withdrawal symptoms from opiates may pass relatively quickly, they do not feel quite right for several weeks or even months thereafter. Called the „protracted abstinence syndrome,“ this cluster of vague depressive-like symptoms can include reduced concentration, low energy level, poor sleep quality, and anhedonia.

New data in animals, reported in Biological Psychiatry, now implicates the serotonin system in this phenomenon.

French researchers found that mice with chronic morphine exposure showed decreasing physical dependence during a period of abstinence, with no physical withdrawal symptoms after 4 weeks. In contrast, low sociability and despair behavior clearly developed after 4 weeks of abstinence.

Remarkably, treatment during the abstinence period with the antidepressant fluoxetine prevented the development of both social aversion and despair behavior.

This is important because fluoxetine targets the serotonin system, which is known to influence mood.

Senior author Dr. Brigitte Kieffer explained that this study „establishes a direct link between morphine abstinence and depressive-like symptoms, and strongly suggests a causal effect of serotonin dysfunction in depressive features associated with abstinence.“

„The greatest risk associated with protracted abstinence is relapse to drug use,“ comments Dr. John Krystal, Editor of Biological Psychiatry. „This study provides new insights into a process that may contribute to relapse.“

These findings should foster novel research along serotonergic pathways in drug abuse. It is hoped that these findings can lead to real-world clinic use, since serotonergic medication is already broadly available.

 

source; http://www.sciencedaily.com/releases/2011/02/110201083930.htm

Abstract: Self-injurious behavior (SIB) is a primary reason that individuals with
neurodevelopmental disabilities (NDD) are either retained in restrictive environments or
are administered psychotropic medication. There are no known causes and no universally
accepted treatments for this complex behavior among individuals with NDD. There is
developing evidence, however, that individuals exhibiting SIB have a disturbance of the
opiate-mediated pain and pleasure system. One hypothesis is that SIB reflects insensitivity
to pain and general sensory depression (hypoalgesia), perhaps related to chronic elevation
of endogenous opiates. For instance, many self-injurious individuals do not exhibit the
usual signs of pain after their “injurious” behavior. Moreover, for some individuals the
addictive properties of elevated endogenous opiates (euphoria) may be responsible for
maintaining their SIB. In this perspective, SIB may be viewed as an addiction because it
supplies the „fix“ for tolerant, down-regulated opiate receptors. Reports that levels of
endogenous opiates at rest and after SIB episodes predict positive responses to opiate
blockers (e.g., naltrexone) provide further support for opiate-mediated SIB and form the
basis for a rational treatment strategy. Although the long term effects of opiate blockers on
SIB are unknown, reduction in SIB following acute treatment provides support that a specific
biological system may be dysregulated in a subgroup of patients. It is concluded that
naltrexone produces a clinically significant reduction in the serious and life-threatening
behavior of self injury for individuals who have not been responsive to any other type of
treatment. Several suggestions and cautions are provided for regimens of naltrexone
treatment of SIB.

1. Introduction
Despite considerable research effort, self-injurious behavior (SIB) continues to be a primary reason,
together with aggression toward others, that individuals are either retained in institutional (restrictive)
environments or are administered psychotropic medication. Today, SIB remains unmanageable,
expensive ($150,000–$500,000/year/patient in institutional settings, with national costs well over
$3,000,000,000 [1]), and is often life threatening. It is surprisingly prevalent, occurring in ~30% of
individuals with developmental neurological complications, including those with autistic disorders [2,3].
Twenty-five experts invited by the National Institute of Child Health and Human Development
(NICHD) to discuss the relations among the genetic, neurobiological, and behavioral causes and
treatments for SIB reached two general conclusions. Intentional acts of harm to self, evident in many
species, (a) have no known cause and (b) no agreed upon treatment [4]. The apparent absence of
visible progress in understanding or treating SIB is not because of a lack of interest or effort. Studies of
self-injury have increased exponentially over the past 30 years, rising from just 60 published studies
between 1980 and 1984 to over 1,700 studies reported between 2005 and 2010 (Figure 1).
Figure 1. Number of studies of self-injurious behavior (SIB) conducted in 5-year intervals
from 1980 to the present.
One major obstacle in understanding the mechanisms of SIB and developing coherent treatment
plans is the absence of distinctive behavioral phenotypes. Despite the consensus that SIB has variable
expression with no known cause, the group of NICHD experts agreed that SIB could be defined,
perhaps with greater precision than most complex human behaviors. SIB is a directly observable

behavior that can be reliably counted. The NICHD group argued that data collection and analysis had
advanced so that complex patterns of SIB should replace or supplement measures of rate and
frequency [5,6]. Two distinct patterns of SIB were proposed as possible guides. One pattern consists of
bouts that are most likely maintained by environmental contingencies. The second pattern involves
protracted periods of SIB that are most likely under the primary influence of biological factors. The
vast majority of existing studies, however, have reported frequencies or rates of occurrence of SIB
often linked to a single environmental manipulation. It is a significant advantage that many forms of
SIB can be counted and time-stamped enabling contemporary studies to use sequential and time series
procedures to define their structure and their relations with other behaviors and the environment. We
subjected extensive and lengthy observations of maladaptive behavior in its natural environmental
context to time series analysis and discovered unique temporal and sequential patterns of these severe
maladaptive behaviors [2,3,7-10].
Specifically, we found for a large majority of the individuals studied, SIB was predicted only by its
own recent history. In our cohort of severely self-injurious patients, SIB was expressed consistently in
successive occurrences revealing a unique pattern of sequential dependence compatible with a
“contagious” distribution. Application of time-series methods of analysis that controlled for chance
pairings of events indicated that the contagious patterns of SIB were independent from frequency and
rate of occurrence. That is, the temporally dependent patterns we observed were not a function of high
rates of occurrence. Moreover, and surprisingly, SIB was not associated consistently with other
behaviors or with the several staff activities or environmental conditions recorded in these studies.
Thus, in a significant majority of these individuals, SIB episodes were self-perpetuating and not related
to antecedent or subsequent environmental circumstances, events, or other recorded behaviors.
This novel and surprising finding was consistent with conclusions of the NICHD group that some
expressions of SIB may have an underlying biological basis because a solely self-perpetuating
behavior is most parsimoniously explained by internal (i.e., biological) motives [2,11-13]. The vast
majority of individuals in our cohort exhibited the most primitive level of internally regulated behavioral
patterns despite years of behavioral interventions and treatment with various medications [8,9].
Anecdotal and clinical observations of these individuals also strongly suggested a biological basis for
their behavior and specifically involvement of the pain and pleasure systems. Typically, SIB is
repetitious consisting of hourly, daily, weekly, monthly, or even yearly cycles [14]. Some individuals
who repeatedly injure themselves appear immune to the normal experience of pain [12]. They abuse
and injure their bodies, hitting or biting themselves, hurling themselves to the ground, and banging
their head against solid objects resulting in broken bones, disfigurement, blindness, and even loss of
life [2,15,16]. They often work to overcome interventions designed to decrease self-injury in a manner
that is consistent with seeking positive reward. For instance, protective devices (such as helmets) may
result in individuals exerting greater effort and exhibiting greater rates of behavior to hit and harm
themselves [17].
Because many medications that treat pain or induce pleasure are addicting, it is interesting that SIB,
in addition to the obvious involvement of pain systems, shares features of addiction such as
compulsive and ritualistic (or stereotypic) patterns that either comprise or surround the self-injuring
acts. One biological system that has been implicated in SIB and the modulation of pain and pleasure is
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the hypothalamic-pituitary-adrenal (HPA) stress axis and specifically the proopiomelanocortin (POMC)
molecule [3,18,19].

2. The Biological Stress System Pain, Pleasure, and SIB
Thompson and Caruso [6] recognized that some forms of SIB were “neurochemically driven and
independent of environmental events.” Early studies either of basal or of resting levels of a variety of
peptides, proteins, transmitters, and amines in plasma or cerebrospinal fluid from patients exhibiting
SIB, however, generated inconclusive results. This was not surprising because there was little
consistency among studies regarding the rigor of diagnosis, the molecule measured, the tissue assayed,
or the conditions assessed [20-26].

2.1. Pain and the Endogenous Opioid System
Although it is not a universal observation, most self-injurious individuals do not exhibit the usual
signs of pain after their “injurious” behavior. Despite inflicting serious physical damage to their bodies,
many of these individuals do not grimace, cry, or show other symptoms that they are experiencing pain.
It has been suggested that this absence of response to self-inflicted injury reflects insensitivity to pain
and general sensory depression induced either by elevated endogenous opiates or by supersensitive
opiate receptors [11,27-29]. This possibility is supported by classical findings that opiate receptor
blockers (a) reverse congenital insensitivity to pain [30]; (b) normalize hypothalamic-peptide
dysfunction coexisting with elevated pain threshold [31]; and (c) increase brain responses to sensory
information [32]. These observations are consistent with a venerable animal literature proving that
opiate blockers lower pain threshold [33]. In summary, these findings support an analgesia (or pain)
hypothesis that implies that self-injurious individuals do not feel pain because of chronically elevated
endogenous opiates and/or opiate receptor downregulation.
2.2. Pleasure (Addiction) and the Endogenous Opioid System
It also is possible that the addictive properties of elevated endogenous opiates are responsible for
maintaining SIB. If it is presumed SIB does result in pain and that the experience of pain results in the
release of opiates, then it can be argued that individuals commit self-inflicted harm to receive the
euphoric (pleasurable) effects of increased circulating opiates. From this perspective, SIB is an
“addiction” to the endogenous opiate system because its consequences supply a “fix.” It has been
known for over 25 years that endogenous opiates have addictive properties as indicated by the
development of tolerance [34], physical dependence [35], and euphoric-like effects [36] after repeated
administration. The repetitive, often compulsive, and ritualistic patterns of SIB (i.e., injury to one area
of head or body, stereotyped patterns of behavior, and catastrophic responses if the environment is
slightly changed) are similar to rituals and compulsive patterns often associated with addictive
behaviors. The addiction hypothesis maintains that individuals with SIB may endure the pain to enjoy
the pleasure it produces as well as to avoid a withdrawal effect. The addiction hypothesis predicts that
SIB may be reinforced both positively and negatively because it gains the individual access to the
narcotic effect of endorphins while simultaneously allowing the individual to escape the unpleasant
sensory consequences commonly associated with the absence of opiates following chronic and
sustained access.
2.3. Stress and the Endogenous Opioid System
The endogenous opioid system is tightly coupled with the general stress response. Evidence from
several laboratories indicates that functioning and processing of a stress-related molecule (POMC) in
the HPA axis may be perturbed among subgroups of individuals exhibiting SIB [15,19,21,37-43]. In
humans, most POMC is produced in the pars distalis of the anterior pituitary but also by hypothalamic
neurons and neurons in the amygdala and pituitary stalk. POMC is a well-characterized 31-K dalton,
bioinactive protein-like molecule that is post-translationally converted by enzymes (e.g., PC1 and PC2)
into biologically active fragments, including B-endorphin (BE) and adrenocorticotropic hormone (ACTH)
[15,44-48]. Normally, BE is coreleased from the anterior pituitary with ACTH in response to a variety of
stressors. However, elevated BE but not ACTH is associated with SIB either at rest or after an episode of
SIB [3,12,18]. This suggests that one consequence of SIB is the disregulation of the arousal system. The
validity of these hypotheses is not known but they have encouraged treat-ments, including opiate
receptor blockers, designed to regulate the opiate/stress system as means to control SIB.
3. Efficacy of Opiate Blockers in the Treatment of SIB

3.1. Acute Effects of Naltrexone
In a review of pre-1991 studies [49], six of eight published studies reported that injectable naloxone
significantly reduced SIB. In these eight studies, naloxone was tested in a total of ten individuals with
SIB. A decrease in SIB was reported for seven individuals. In that same review, 12 published studies
of naltrexone (Naltrexone) in MR/DD individuals were summarized. Most of the studies either were
case studies or were studies with very small samples. At that time, 45 MR/DD individuals (at least 28
with SIB) had been treated with naltrexone and 38 individuals had positive responses of various
degrees including a reduction in SIB in 24 of the 28 patients. A separate review of 13 studies
(including several in the Sandman review [49]) concluded that about one-third of the patients tested
with Naltrexone had a decrease in their SIB [50]. Several studies in this later review included juvenile
patients under the age of 8 years [51] and patients with primary behavioral problems related to
aggression and agitation [52]. Aggression toward others and agitation are not equivalent to SIB on any
obvious dimension except, perhaps, exertion, and the fact that opiate blockers were ineffective in the
control of these behaviors adds inferential support to the argument that the opioid system is uniquely
implicated in SIB and not in other maladaptive behaviors. The effects of opiate blockers in children
who self-injure may be similar to the effects observed in adults but there are too few reports to make
that conclusion.
More recently, a thorough review of the scientific literature employing stringent and appropriate
criteria for inclusion concluded that the effects of opiate blockers on SIB could be evaluated in a total
of 86 patients [53]. Eighty percent of the subjects were reported to improve relative to baseline
(i.e., SIB reduced) during naltrexone administration. Of the subjects who improved, 47% exhibited a
reduction in SIB by 50% or greater. In studies reporting dose levels in milligrams, males were more likely than females to respond. No significant relations were found between treatment outcomes and
autism status or form of self-injury.
Two relatively large, placebo-controlled studies [16,54] included in this review of naltrexone came to
very similar conclusions. In a double-blind, placebo-controlled, dose-finding study, Sandman et al. [54]
reported that 18 of 21 individuals exhibiting SIB responded favorably to at least one dose (range of
0.5–2.0 mg/kg) of naltrexone (time-sampled video records provided direct observations of the subjects).
Acute treatment (1 week at each of three doses) with naltrexone reduced the frequency of SIB without
major side-effects. Activity, stereotypy, involuntary movement, and neurological status were not
influenced by naltrexone. There were two central findings. First, the highest dose (2 mg/kg) was the most
effective, confirming earlier results in this population [55,56]. Seven of the eight patients responding best
at the highest dose, also responded favorably to the 1 mg/kg dose. Six of these eight patients also
responded at the 0.5 mg/kg dose. Eleven subjects responded positively to both the 1 and 2 mg/kg doses.
Second, subjects with the most frequent SIB were the most positive responders to higher doses of
naltrexone, consistent with earlier reports [55,56]. A small minority of subjects responded most
favorably to lower doses. These results confirmed that at least 50% of the individuals with SIB
responded favorably to treatment with opiate blockers.
Another double-blind, placebo-controlled, fixed-dose study of eight, severe to profoundly retarded
adults included in the review [16], reported that treatment with naltrexone reduced head hitting, head
banging, and self-biting. The eight individuals evaluated displayed 18 forms of SIB. Improvement was
observed in 77% of the head hitting and head banging episodes and 100% of the self-biting forms.
Episodes of high frequency SIB also were more sensitive to treatment with naltrexone. The 100-mg
(high) dose was more effective than the 50-mg (low) dose in reducing SIB. For several individuals,
some forms of SIB decreased after naltrexone (e.g., head hitting and self-biting) but other forms
(e.g., throat poking) did not change. Four of the subjects in this trial received concomitant treatment
with clonidine (alpha-2-adrenergic agonist) but no effects on SIB or interactions with naltrexone were
observed. These findings compliment previous studies and caution that although naltrexone is effective
in reducing SIB, not all forms of self-inflicted harm may be controlled by blocking the opioid system.
These two relatively large studies of acute treatment with naltrexone came to very similar
conclusions. Opiate blockers appear to be an effective treatment for a significant number of individuals
exhibiting SIB. Administration of naltrexone reduces high frequency SIB and some, but not all, selfdestructive
behavior. Both studies acknowledged that not all individuals expressing SIB were positive
responders and that a small minority may increase SIB (see also Barrett [57]).
In the single study that has evaluated the effects of naltrexone using time-series analysis,
Symons et al. [58] made very interesting observations. First, they reported that three of the four patients
evaluated had at least a 33% reduction in their SIB. (The fourth patient had a 17% reduction in SIB.)
Second, and most interesting, they discovered that in addition to the improvement with naltrexone,
there was an alteration in the sequential dependencies between staff behavior and the manifestation of
SIB. During treatment with naltrexone, there was a significant increase in the probability that staff
would “prompt” individuals proximal in time and sequence to an SIB event for three of the four
patients, and a significant decrease in the fourth. One possible conclusion from these findings is that
naltrexone exerts its effects on SIB, in part by the opioid-mediated reinforcing influences of social
interactions. Alternatively, Symons et al. [58] suggest that SIB may be “multiply determined such that
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naltrexone may diminish opiate-mediated SIB leaving socially mediated SIB unchanged.” The overall
clinical implication is that many cases of SIB may be subserved by both opiate- and socially mediated
processes and that effective treatment for such cases would require a combination of naltrexone with
behavioral intervention strategies.

3.2. Long-Term Effects of Naltrexone Treatments
The long-term effects and consequences of continued treatment with naltrexone is not completely
known because most studies reporting treatment of individuals with SIB have been short-term
demonstrations or acute trials. Most published long-term studies have been either case studies or openlabel
designs and they have generated mixed results. Two types of studies comprise the long-term
evaluations of naltrexone, either prolonged treatment with naltrexone or extended observations
following brief periods of treatment. With these procedures, investigators have reported that about six
of eight patients examined in several studies exhibited long-term benefits in varying degrees from
treatment with naltrexone [57-59]. In the first report, a total of 24 days of naltrexone treatment resulted
in elimination of SIB in a 12-year-old girl that persisted for at least 22 months [57]. A similar finding
was reported after 1 year of continuous treatment with naltrexone in a 28-year-old woman with severe
SIB. Not only did treatment eliminate SIB but also the near-zero rate persisted through placebo and nodrug
phases of the study [59]. In their retrospective study of 56 patients, Casner et al. [60] discovered
that 57% of their patients treated with naltrexone between 3 and 878 months were considered to be
positive responders and 25% of these met objective criteria as responders.
We [61] examined the long-term (12 month) effects following acute treatment with naltrexone and
then we assessed the effects of subsequent long-term treatment with naltrexone. To accomplish this,
we enrolled 15 subjects in a double-blind, placebo-controlled acute dose-finding study. Each acute
dose was evaluated for a 1-week period with placebo weeks interspersed. Subjects were followed for a
12-month period and then they were enrolled in a multiple baseline design with a single most effective
dose (determined in the acute phase) administered to each subject for 2-, 3-month periods over an 18-
month interval with placebo periods appropriately separating the treatment phases. Again, timesampled
video records were scored using a computer-assisted program [62].

The primary finding from our study was that a subgroup of patients exhibited persisting effects
(decreased SIB) in the 12 months after acute treatment with naltrexone. Seven patients exhibited
decreased SIB over the 12-month period and five of these had a 75% reduction in SIB compared to the
placebo control period. These five patients, each with at least a 75% reduction in SIB, increased their
SIB when administered naltrexone in the long-term treatment protocol. The largest decrease in SIB was
observed in patients who had a brief exposure to naltrexone, were given a 12-month hiatus during which
they showed an increase in SIB, and then were readministered naltrexone several times in the 18-month
double-blind, placebo-controlled study.

4. Endogenous Opioid Levels Predict Response to Opiate Blockers
In our initial study to examine the relation between circulating endogenous opioids and response to
naltrexone, we collected blood samples from ten patients within 2–5 min of a self-injuring act and
during a control period [18]. At least 1 month later patients were administered three different doses of naltrexone in a double-blind, placebo-controlled crossover study over a 10-week period. All patients
were videotaped during the study and behavior was coded with a computer-assisted program. Patients
with the highest change in plasma levels of BE after SIB had the most and statistically significant
positive response to naltrexone. These results were consistent with several other reports. First,
Ernst et al. [21] reported that baseline levels of BE were positively related to changes in behavior
(clinical global impressions, CGI) after treatment with naltrexone in five young autistic children.
Second, Bouvard et al. [38] found that C-terminal BE decreased after naltrexone only in good
responders. Third, Scifo et al. [63] found that increases in SIB and response to naltrexone in some
patients, were related to high levels of endogenous opiates (i.e., good responses to naltrexone were
observed in patients with high levels of BE). Fourth, Cazzullo et al. [64] reported that patients
responding with decreased BE levels after treatment with naltrexone had better and more pervasive
behavioral improvement than patients who did not have physiological changes after naltrexone.
In a follow-up study of nine additional patients (total of nineteen), we [3] found that plasma BE was
uncoupled from the usually coreleased ACTH [65-71] after an episode of SIB. This unusual pattern was
not a function of time of day that blood was sampled, and it confirmed our earlier observations [7,18]
and provided additional support for this specific biological marker among a diverse group of subjects
who share a behavioral aberration. In addition, stronger support was generated for the effectiveness of
naltrexone in reducing SIB.
Positive responses to low doses of naltrexone were observed in subjects who did not exhibit
increased BE after SIB. That is, low doses of naltrexone were effective in reducing SIB only in
subjects either who did not exhibit a surge in BE after SIB or whose baseline level exceeded the level
after SIB. The relation between BE and response to the lowest dose of naltrexone was consistent with
our earlier results, and statistically significant with the addition of nine subjects. Previously we [3] suggested
that SIB had functional significance because it increased endogenous opiates and thereby
delivered positive consequences (i.e., pleasure/euphoria/pain modulation). We argued that the highest
dose of naltrexone most effectively blocked this mechanism in subjects with the highest levels of BE
after SIB. The results from the follow-up study suggested an alternative possibility related to baseline
levels of, or baseline relations between, POMC peptides. Because the lowest dose of naltrexone was
most effective in subjects with the highest (morning) baseline (relative to post-SIB) levels, we
speculated that the association between baseline ACTH and BE could influence the response to
naltrexone (based on evidence that supported reciprocal functions of BE and ACTH [72]]. If our
speculations were accurate, subjects with the greatest difference between morning BE and ACTH
levels would be the most responsive to low doses of naltrexone because there would be less attenuation
of the opioid influence. The test of this possibility confirmed our speculations because we found that
subjects with high levels of morning (chronic) BE and low levels of ACTH were associated with positive
responses to the low dose of naltrexone. This possibility may be compatible with findings that chronic
exposure to opioids resulted in supersensitivity to the effects of low doses of opiate antagonists [73,74].
These findings have since been extended using a fundamentally different method for quantifying
changes in the temporal patterning of SIB following treatment with naltrexone. The THEME method
developed by Magnusson [75,76] has been used to detect highly significant, nonrandom, hierarchical
patterns in the temporal organization of SIB with respect to other observed behaviors. Kemp et al. [10]
reported that these temporal patterns (“T-patterns”) of SIB were significantly correlated with basal
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levels of BE. In the subgroup of subjects receiving naltrexone (discussed above), the percent change in
these T-patterns of SIB (between weeks the subjects were receiving placebo and weeks they were
receiving naltrexone) was found to be significantly correlated with post-SIB (i.e., samples were
collected immediately after SIB) levels of the N-terminal fragment of beta-endorphin (βEN). No such
correlations were found for changes from placebo on any “control” T-patterns (those containing noninjurious,
stereotyped behaviors or staff interactions) nor for any samples collected during other
periods. These results are shown in Table 1.
Table 1. Pearson’s r coefficients (significance) between levels of beta-endorphin (Nterminal)
collected in either the AM, PM, or following SIB, no SIB, or physical exercise
(PE) and the change in the percentages of T-patterns (by behavior type) for weeks treated
with placebo and naltrexone.
We have made similar observations in our long-term studies of naltrexone and SIB [19]. POMC
fragments were measured in twelve self-injurious patients before and after long-term (3-month)
treatment with naltrexone. POMC fragments were sampled from blood collected at the end of the
baseline and placebo-controlled treatment phases of the study. Two patterns emerged. One group
(responders) displayed persisting improvement in SIB and lower relative levels of BE after initial
exposure to naltrexone. Chronic administration of naltrexone to this group was associated with
increased SIB and elevated relative levels of BE. Return to placebo improved their behavior (reduced
SIB) and their levels of BE returned to basal levels. The second group (nonresponders) was
characterized by absence of persisting improvement after acute treatment with naltrexone and by
elevated basal BE levels. Chronic treatment with naltrexone improved their behavior but did not alter
their BE levels. Long-term positive responders to acute doses of naltrexone were associated with less
disregulation of ACTH and BE.

5. Conclusions
When it was established that the body had its own opiate system [77], the endogenous opiates
became prime suspects responsible for maintaining SIB. Perhaps individuals who self-injure have
elevated thresholds for pain or derive pleasure from painful stimulation. Exposure to, or levels of,
endogenous opiates could explain these possibilities. Reduction in SIB following treatment with opiate
blockers would provide evidence for the opiate hypothesis of self-injury. Results from studies to test
these possibilities, however, are complex. The complexity is related primarily to the fact that patients
exhibiting SIB and evaluated after treatment comprise a mixture of etiologies, pathologies, and
motivations. Despite the tremendous amount of error introduced with a heterogeneous population,
there is substantial evidence that opiate blockers are efficacious in reducing SIB.
Beta-Endorphin (N-terminal) Levels
Change in T-Pattern % by Type: AM PM Post-SIB No-SIB Post-PE
SIB 0.37 (0.47) 0.25 (0.64) 0.82 (0.04) −0.45 (0.44) 0.66 (0.22)
Stereotypy −0.76 (0.07) −0.26 (0.96) 0.52 (0.29) −0.29 (0.64) −0.10 (0.87)
Staff Interactions 0.42 (0.41) 0.54 (0.27) 0.35 (0.49) −0.63 (0.25) 0.26 (0.68)
The observations that opiate blockers reduce SIB are important for at least two reasons. First,
naltrexone produces a clinically significant reduction in a serious and life-threatening behavior for
some individuals typically who have not been responsive to any other type of treatment. We have
observed startling improvements in individuals who have failed all rational treatments. Some adults in
our studies have had protective headgear discontinued for the first time since early childhood. Others
have developed adaptive skills and have acquired the ability (or the privilege) to leave institutions for
the first time in their lives after treatment with naltrexone. Second, the results with naltrexone are
important because they suggest that a specific biological system may be disregulated in a subgroup of
patients. Because the opiate blockers have few effects in the absence of opiates [78], effective
treatment with these drugs must engage the endogenous opioid system. Reports that resting levels of
endogenous opiates or levels of endorphin after an SIB episode predict positive responses to opiate
blockers provide support for this assumption and the foundation for rational treatment strategies based
on biological criteria.
From the current review we can draw several conclusions. There is consensus in the literature that
doses between 1.0 and 2.0 mg/kg or a fixed dose of 100 mg are the most effective for reducing
SIB [16,53,54]. At these doses, at least half of the chronically self-injuring patients exhibit at least a
25% reduction in their behavior. It is important to acknowledge that the studies that have reported
reductions of 25% or greater, typically conducted direct observations of the patients and did not rely on
global clinical ratings. As reviewed by Symons et al. [53], male patients respond more favorably to
naltrexone treatment than do female patients. There is consensus that naltrexone is a safe drug without
major or contraindicating side effects. Most individuals entered into naltrexone trials exhibited the
most severe SIB for which all other forms of treatment had been ineffective. Often their behavior
presented life-threatening consequences and always their SIB prevented them from enjoying a less
restrictive environment. Against this background, the possible benefits of reduced SIB by treatment
with naltrexone exceed the risk of side-effects. We are aware of clinical decisions to treat SIB with
naltrexone even when patients presented with risk factors such as chronic hepatitis [79]. To our
knowledge, there have not been serious side effects solely due to administration of naltrexone among
MR/NDD patients. There is consensus among the studies that naltrexone is an effective treatment
because the endogenous opioid system is engaged by SIB [3,16,18,19,57]. SIB has characteristics that
resemble addictive behavior (compulsive, ritualistic, destructive) and altered pain threshold. Both of
these characteristics implicate the opioid system and support the logic of opiate blockers as reasonable
treatments. There is consensus that long-term treatment of SIB with naltrexone apparently is not
harmful and may be effective. There is consensus that generally, treatment with naltrexone appears to
be effective in about half of the adult patients examined. Following effective acute treatment with
naltrexone some patients have shown a rebound to pre-treatment levels [61]. There is consensus that
naltrexone should be avoided during periods when patients are known to be in pain requiring narcotic
analgesics, such as surgeries or with bone fractures. Alternately, nonnarcotic analgesics should be
administered to patients receiving naltrexone [80]. Finally, it should be noted that there are reports of
paradoxical increases of SIB following treatment with naltrexone [81]. In our own research [61], we
have observed increased rates of SIB in individuals who showed sustained improvements throughout a
12-month hiatus following a brief period of acute treatment with naltrexone, and then were given longterm
treatment (3 month) with naltrexone.

Acknowledgements
This research was supported by award HD-48947 from the National Institute of Child Health and
Human Development. The assistance of Mohammed Lenjavi and Paul Touchette is gratefully
acknowledged.

 

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