Scientific Basis

Detailed Scientific Basis For Using Psychotropic Analgesic Nitrous Oxide For Addictive Withdrawal States
Scientific work indicates that PAN is the most effective, rapid and safest method of detoxifying mild to moderately severe alcoholic withdrawal states[1-20,20a] (AWS). PAN has also been successfully employed for addictive withdrawal from opioids, cannabis, cocaine and nicotine [4,6,8,10,15]. This work was done over the last 20 years on over 25,000 chronic alcoholic patients that would satisfy DSM-IV criteria for alcohol dependence syndrome. Many of these patients were treated at the largest dedicated alcoholic rehabilitation facility in Southern Africa in Johannesburg (Wedge Gardens, Rand Aid). Over the last 15 years approximately 6,000 patients have been treated at Themba Center Transvaal South Africa (a dedicated in-patient alcoholic facility) and Madadeni Hospital, Kwa Zulu-Natal, South Africa (a 1400 bed general and psychiatric hospital in Natal)[16].

Advantages of PAN
PAN was also introduced to Helsinki, Finland in March 1990, where it has proved an excellent therapy for AWS and other addictive withdrawal states[17,18]. Published research[1-20,20a] indicates the following:-

• The PAN regime is much more rational for treating the AWS than any currently available benzodiazepine (BZ) regime. Unlike the BZ it not only controls the hyperadrenergic state but also stimulates the underactive endogenous opioid system (see Mode of Action of PAN; page 24) The PAN is therefore able to simultaneously restore the balance between overactive and underactive systems. It therefore hastens a return to pre-withdrawal homeostasis.It is for this reason that the effects of the gas, even after a single 20 minute period of administration,is sufficient,in most cases,to carry the patient through the full detoxification period without relapse or rebound and with minimum adjuvant sedative medication.
• Because of its pharmacokinetic properties it is also possible to titrate the dose of PAN for each individual patient very accurately within a very short time span, usually, less than 10 minutes. As a result the operator is able to avoid over or under medication. Such accurate titration is difficult with BZ.
• Because placebo (oxygen) is given immediately on admission it is possible to decide after only 20 minutes whether a non- pharmacological treatment is likely to be effective. Placebo non-responders can then immediately receive PAN, which in the vast majority of cases produces a beneficial effect.Thus the gas method is able to maximize the placebo response and in 30-60% of cases pharmacological agents are avoided.
• It is safer for the above reasons and also because it has much fewer side effects than BZ and other drug therapies.
• PAN produces extremely rapid amelioration of the AWS, much quicker than any other AWS therapy including the BZ. This amelioration usually occurs, literally within minutes of the start of gas administration. As a result, patients are able to rapidly abandon the sick role and enter the rehabilitation program much sooner. Usually at least 48 hours before those treated with BZ.
• In 90-95% of cases a single administration, on admission, is adequate to control the symptoms for the entire detoxification period. In 5-10% of cases the gas is given once again if symptoms recur.
• In the small number of patients who fail to respond to the initial administration of gas more intensive therapy is given and the patient is then regarded as having been recalcitrant to the PAN therapy. For this reason the PAN therapy is an excellent screening test for those few patients needing much more intensive therapy. It is therefore, almost ideal for out-patient therapy.
• Apart from its extremely rapid activity in reversing the AWS the treatment is extremely safe and leads to a marked reduction in addictive sedative and other medications. If required at all, sedatives (oxazepam 15-60mg, nocte) are limited to one or two nights only.
• Because of reduced adjuvant medication requirements and its unusual route of administration it diminishes the reinforcing effect of oral and injection therapy.
• It is favoured by nursing staff provided they have received a short 5 day hands-on training course. Patients require less physical nursing because of the rapid and sustained recovery, placing less stress on themselves and staff.
• Patients prefer it because they feel better almost immediately and can enter the next stage of the rehabilitation program more rapidly. There is also a backlash against the use of tablets and injections by patients, who recognize the dangers of secondary addiction.
• It is also more economical, in terms of medication, nursing requirements, speed of discharge and bed occupations.

 

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Safety of PAN
Nitrous oxide has been used for more than a century for anaesthesia and has an unrivaled safety record for this application[7,21,21a,21b,22c]. However for analgesic doses it is used at much lower concentrations, with at least 30% oxygen at all times. For this reason it is not an anesthetic technique and the patient is conscious and co-operative throughout the administration. Since the patient is not anesthetized and is awake, the precautions associated with anaesthesia are not required, nor is a specialist anesthesiologist needed. In fact it has been approved for use in routine dental practice as a non anesthetic technique and is employed for dental relative analgesia (or inhalation sedation) in the U.S.A. and in many other countries. This approval allows dentists to operate and simultaneously administer PAN himself/herself without another dentist or anesthetist being present. In the U.S.A. alone,in the last 20 years, at least 200 million patients have received PAN “without significant reports of morbidity”.[21] This record leads to the conclusion that, “…properly used nitrous oxide is one of the safest drugs available in clinical practice”[21]. In Denmark where serious complications and death must be reported to the department of health, approximately 4 million treatments of PAN have been administered without a single serious complication being reported[22]. PAN is extremely safe and easy to use, provided the correct equipment (e.g. Dental Relative Analgesia Machine, MATRX Medical) is used after a simple hands-on training course extending over 5 days. This is illustrated by the fact that suitably trained nursing staff are now competent to administer the treatment all over South Africa and elsewhere.

Apart from its use in dentistry PAN has been used for many years as a safe and effective obstetrical analgesic[23]. PAN has also been used safely and successfully for:-

• Minor surgery in pediatrics[21a,21b,24,25].
• Terminal refractory pain[26].
• Control of myocardial pain[27-29].
• Interventional radiology[30].
• Cataract surgery[31].
• Investigation and treatment of neuropsychiatric conditions[8].
• Emergency pain relief[32,33]
• Lumbar Puncture[21a,21b]
• Gastroscopy[21b]
• Bronchoscopy[21b]
• Bone marrow aspiration[21a,21b]
• Venous puncture[21a,21b]

This wide application to patients of all ages and health status indicates its safety. Furthermore, when used for less than 60 minutes continuously at analgesic concentrations it is completely non toxic[7]. PAN “…has no clinically significant effect on respiration, on the cardiovascular system, on metabolism, on renal function or on hepatic function [31].” The only complication, is bone-marrow depression as a result of the inactivation of vitamin B12 which is a co-factor of methionine synthase[7]. However dyshemopoeisis only occurs after at least 60 minutes of exposure to PAN and then only in the extremely debilitated[7]. Therefore dyshemopoeisis has no clinical significance whatsoever for this use of PAN. For treating AWS, PAN is never applied for longer than 40 minutes and then not continuously. Even in the rare case that a second administration is required, the second dose is given for 20 minutes only and is separated by some hours from the first[7]. In healthy subjects continuous exposure of at least 5 hours is required for signs of bone-marrow depression to occur[7]. Experimental findings indicate that even after 60 minutes of continuous exposure to PAN, alcoholic subjects show no additional adverse changes caused by the PAN, despite their underlying disturbed marrow function[7].

Clinical observations in over 25,000 cases treated by SABRI physicians and others support the lack of toxicity of PAN when used to treat the AWS. There has been no evidence of bone-marrow suppression attributable to the gas despite regular, random monitoring of peripheral blood smears. Animal studies support these conclusions regarding the safety of PAN for treating AWS. Despite exposure of aging rats to chronic ethanol administration plus 6 continuous hours of 60% nitrous oxide, the gas did not act synergistically to produce disturbances in folate and vitamin B12 metabolism[34]. A combination of an acute dose of alcohol (3g/kg) and 4 hours of exposure to 66% nitrous oxide in oxygen also did not have a synergistic effect on the inactivation of methionine synthase activity in rats[35]. These findings are especially noteworthy since rodents are more sensitive to methionine synthase inactivation than man[36].

There is evidence from animal work that there is cross tolerance between PAN and alcohol[37,38]. Clinical experience in over 25,000 cases of AWS treated successfully with PAN indicates that this holds true for human subjects. It may explain the reason for patients highly tolerant to alcohol usually requiring higher doses of the gas than those who are less tolerant.

The addictive potential[23a] of PAN is extremely low and has been dismissed as follows by Layzer “It seems unlikely that, as a drug of abuse, nitrous oxide ever will compete seriously with the array of potent mind-altering drugs that are available in much more convenient forms…”[23]. More recently the low abuse potential has been described[39]: “It would appear that it (PAN) is unlikely to become, has never been, nor is it at the moment of any real significance as a drug of abuse when compared to the currently available drugs which clearly pose a much greater problem.” Its lack of addictive potential may be related to its evanescent euphoric effects and partial agonistic profile[4,39]. Not a single case of gas seeking or addictive behaviour has been observed in the cases treated by SABRI physicians or at any of the other facilities to-date[39]. This cohort now exceeds 25,000.

It is of some importance to assess the interaction of PAN with alcohol. The clinical use of PAN for treating well over 25,000 cases of AWS by various investigators has revealed no untoward effects directly attributable to the gas for this indication. In this cohort PAN has not interacted negatively with any of the agents commonly employed for treating the AWS including BZs, barbiturates, chlormethiazole, carbamazepine, phenytoin, clonidine, beta-blockers and major tranquilizers. PAN has been combined with numerous pharmacological agents including intravenous BZs and barbiturates for both anesthetic and conscious sedation techniques without any untoward drug interactions[40-43]. It has also been used millions of times in association with other opioid and non-opioid anesthetic agents, for balanced anaesthesia, for over a century, without untoward drug interactions[43]. As an anesthetic, over this time period, no untoward interactions with any other drugs have been noted, including major tranquilizers for neuroleptic anaesthesia[43,44]. In dentistry, many millions of safe administrations of PAN are provided every year with and without local anesthetic agents. These are conducted with and without screening for the concurrent use of other drugs including alcohol. It seems likely that had there been any untoward reaction between PAN and such concurrent medications this would have become evident after almost 150 years use in medicine. This is particularly so since PAN has been used for conscious sedation in dentistry over many years without a single case of mortality or serious morbidity[45]. Because PAN is a mixture of nitrous oxide at much lower concentrations than are used for anaesthesia the singular lack of side-effects and drug interactions are probably not surprising in view of the safety of nitrous oxide used for anaesthesia, including its use with numerous other potent agents. In the light of the above, it seems the statement that “Nitrous oxide can safely be used with all concomitant medication the patient may be on.”[46] is a fair reflection of the current knowledge.

Despite a decided bias against[23,25,29] the safety of nitrous oxide, at the higher concentrations required for anaesthesia, Eger and colleagues, after thorough and careful research, were unable to substantiate a case against the continued use of the gas[47]. In the latter work they tested the hypothesis that nitrous oxide “…causes major (e.g. myocardial infarction, neuronal injury, hypoxemia, infection, death) or minor ( e.g. nausea, vomiting, headache, earache) in patients…” The work of Eger et al[47] have, at last ,laid to rest any doubts about the safety of anesthetic and the lower dose PAN, on firm scientific grounds. Thus confirming its “…remarkable record of safety for over a century ” both at anesthetic and analgesic concentrations[7]. To quote a doyen of anesthesiology on nitrous oxide “Few drugs have as good a safety record.”[29]

In view of PAN’s propensity to expand bullae, PAN should not be used in chronic obstructive pulmonary disease[23]. This is the only absolute contraindication for PAN therapy.

In the many thousands of patients treated at the Rand Aid facility a clinical history and physical examination has been adequate to exclude any patient who is likely to be negatively affected by PAN. This is indicated by the fact that at no time has a patient who has received PAN for the AWS demonstrated pulmonary problems either acutely or chronically.

From the above, it is clear that SABRI has introduced and established a new paradigm and technology for treating AWS. In addition it facilitates the safe treatment of AWS, except for delirium tremens, on an out-patient basis. This approach offers, socioeconomic advantages to both patient and health service providers. There is already preliminary evidence that PAN ameliorates withdrawal from cocaine, opioids, nicotine and cannabis[4,6,8,10,15], although further work is required to confirm these indications. In addition, since PAN can be classified as an opioid agonist, further work in this field might be useful. For instance, using more traditional opioid agonists such as buprenorphine. Comparing the effects of PAN and buprenorphine may be help determine the role of the opioid system in the pathogenesis and treatment of AWS and other withdrawal states.

Modes of Action Of PAN
PAN is inhaled, effecting the brain very rapidly. It therefore can be titrated quicker, more accurately and safely than agents given via other routes. Many of the advantages of using PAN, as listed above (see above), are related to its unique pharmacokinetic and pharmacodynamic properties.

PAN is a partial mu opioid agonist[4,39]. As with other opioids like the prototype, morphine, which is histaminergic anticholinergic[48] and adrenergic[49] PAN also has non-opioid properties[50]. These include adrenergic[51], serotonergic[52] and GABA-ergic[53] actions. However, it would seem that the major therapeutic effect of the PAN is through its opioid effect, which counters the well established opioid deficiency state during AWS[3,54,55]. Apart from its direct effect in nudging endogenous opioid system activity towards normal it also attenuates the hyperadrenergic state in the AWS[3]. Nonetheless, PAN has mild adrenergic activity, which conceivably prevents excessive suppression of adrenergic drive. Thus PAN seems to reduce the stress reaction found in the AWS by helping to establish homeostasis between the various neurotransmitter systems.

An earlier hypothesis postulating the presence of 2 mutually antagonistic opioid systems involved in withdrawal, is supported by recent findings.[55a] These show that mu and kappa receptor agonists respectively stimulate and inhibit dopamine (DA) release in the nucleus accumbens (na).[55b] Since PAN is a multipotent opioid receptor agonist[4,5,39] it probably modulates the various opioid receptors controlling DA release in the na. Significantly, it has been shown that in both AWS and morphine withdrawal there is a marked decrease in DA release in the na.[55b,55c]

The positive serotonergic effects of the PAN[52] synergises with its opioid effects to reduce the depression associated with the AWS[3]. PAN also facilitates benzodiazepine activity which has been regarded as a GABA-ergic response at GABAA receptors[53]. This action may account for the cross tolerance between PAN and alcohol[37]; a hallmark of effective treatments for the AWS.

As an opioid PAN decreases acetylcholine release which is usually increased during the AWS[3]. This would tend to prevent resting tremor, overactivity of the reticular formation and aggressive behaviour: all of which have been related to cholinergic mechanisms in the brain[3].

BZs and other sedatives commonly used for the AWS inhibit cyclic GMP[56] production, while PAN enhances it[57].

PAN thus helps to restore homeostasis at both the neurotransmitter and second messenger levels. PAN is the only agent currently available that does not have a purely depressant effect. The latter seems to be the common mode of action of all sedative medications used for the AWS.

The partial opioid agonism and other properties of PAN restores a normal homeostasis much more rapidly than any other treatment presently used. On a theoretical basis, this would account for its extremely rapid therapeutic effect. Even after a single administration, despite its rapid elimination. As is confirmed by the empirical findings[1-20,20a] once homeostasis has been achieved rebound and relapse is rare.

PAN Compared With Other Agents For Alcohol Withdrawal
Major tranquilizers were found to be extremely useful in treating alcohol withdrawal[30]. Their use was generally discontinued because they failed to prevent the development of delirium tremens. Furthermore, it was found that as compared with placebo and BZ they produced a statistically higher mortality rate[31]. It was for these reasons that BZ supplanted the neuroleptics for treating AWS[30,31].

However despite general acceptance as the most suitable agents for treating the AWS, the BZ are not ideal for this indication [60-62]. Very few controlled clinical trials have compared the BZ against other drugs [63]. Indeed,it has been suggested that the notion of the superiority of BZ for treating the AWS is based on “…old and rather badly designed trials.”[64]

For example some patients transfer their addiction from alcohol to the BZ, although some authorities do not regard this as such a serious problem[65]. More recently it has also been shown that those who abuse BZ are likely to have abused alcohol. Moreover onetime alcoholic patients treated with BZ both abuse and become dependent on them[66,67]. Short-acting lipophilic drugs like lorazepam are preferred to short-acting barbiturates by some addicts[68], indicating the high abuse potential of such agents. In a further study Woods et al indicate a low rate of abuse of BZ in recovering alcoholics[69]. But because no controlled studies have been published on the abuse of BZs in drinking alcoholics these authors also indicate that the concomitant use of alcohol with BZ may increase the risk of physiological dependence on the BZ. In addition, combinations of alcohol and BZ substantially increase the risk of adverse behavioural and other toxic effects of BZ use[69]. Daily use of alcohol, or family alcohol history, may be risk factors in the development of low-dose BZ dependency[70]. The latter point was emphasized when it was suggested that BZ should not be used for treating patients who are abusing alcohol[71]. Such patients should rather receive agents which may be sedative but less attractive as addictive drugs[71]. In fact it has been suggested that the present use of addictive drugs in alcohol treatment facilities makes as many addicts as are cured[72]. This view has led to some alcohol facilities in the U.S.A abandoning the use of BZ entirely for AWS[73].

Of interest therefore, is that over the last 20 or so years, SABRI investigators have noticed a gradual increase in the percentage of patients presenting for AWS treatment, having dual addictions to alcohol and BZ. A factor which complicates the treatment of the AWS and is preferably avoided. It has been said that “… the problem of benzodiazepine dependence among alcoholics cannot be ignored.”[74] Until there is substantive published evidence to the contrary, this caveat is as valid today as it was when first written.

The abuse potential of BZ is not the only problem associated with their use in treating the AWS. Hypotensive episodes can be precipitated by these agents and symptoms such as tremor are aggravated rather than ameliorated[75]. Combinations of alcohol and BZ, even short-acting agents, which on their own do not suppress consciousness, may produce stupor when combined[76]. A study comparing atenelol and oxazepam with oxazepam and placebo showed that BZ can aggravate the AWS[77]. Although the placebo group had higher doses of oxazepam than the other group, behavioural dysfunction (anxiety, hallucinations, agitation) was greater in the placebo-oxazepam group. This was especially marked on the first 2 days, but the deterioration in behavioural signs continued until after the third day. These investigators rationally concluded that the decrease in the use of oxazepam in combination with atenelol was an advantage of the beta-blocker therapy over placebo-oxazepam. Another double-blind study comparing chlordiazepoxide and clonidine in treating the AWS shows the negative effects of BZ[78]. This study showed that while the clonidine group improved at all testing times on cognitive function, the chlordiazepoxide cohort regressed toward pretreatment values at 48 hours. Peak plasma concentrations of BZ are associated with other common untoward effects including “light headedness, lassitude, increased reaction time, motor incoordination, ataxia, impairment of mental and psychomotor functions, disorientation, disorganization of thought, confusion… etc”[79]. Many of these signs and symptoms can occur during the AWS and all can be aggravated by the BZ. Patients treated with BZ remain lethargic, ataxic and confused for several days after the AWS has resolved[80]. BZs also aggravate depression, a common symptom of AWS[81]. These troublesome side effects are not found when PAN is used to treat the AWS. The aggravation of the various signs and symptoms of the AWS caused by BZ may be related to the fact that BZ and ethanol administration both produce a decline in brain cyclic GMP[56]. After alcohol withdrawal there is usually a rebound of cyclic GMP[56]. The use of BZ during the AWS would tend to depress the rebound and conceivably retard recovery presumably because of depressed levels of the second messenger. In contrast, PAN as an opioid, raises cyclic GMP levels[57].

It has been suggested by a National Institute on Alcohol Abuse and Alcoholism (NIAAA) review committee that “…the primary reason for considering PAN as a potentially better treatment for AWS… than benzodiazepines is that they “..have both sedating and addictive properties. However with the introduction of the shorter-acting, less sedating benzodiazepines… concern about using these agents has greatly diminished.” Unfortunately there is no substantive published evidence to support this contention[82]. Regarding lorazepam and oxazepam the agents favoured by the NIAAA review committee. Oxazepam has a slow onset of action[81], which may delay the rate of recovery in the AWS. There is some evidence that oxazepam is less reinforcing than diazepam, however this was not the case with lorazepam[83]. Clearly, on this basis lorazepam is as addictive as diazepam. While there is evidence that oxazepam has a lower abuse liability than diazepam this does not mean that its abuse liability can be ignored. For instance while lorazepam is favoured by abusers in Mauritius, oxazepam is preferred in Australia[84]. Another problem, when considering the use of BZ, is that some patients experience withdrawal even when the BZ dose is tapered[68]. And the withdrawal from short-acting BZs may be more severe than for long-acting agents[85]. The facts are: all BZs have significant abuse potential. That this is still considered a substantial current problem is highlighted in a 1993 publication in which the author states that her “…study confirms that patients in treatment for alcohol abuse or dependence …are at significant risk for BZ abuse …and dependence.” She also warn that ” Although the benzodiazepines are widely accepted as the treatment of choice for alcohol withdrawal symptoms…physicians should be aware of their significant potential for abuse and dependence” in an alcoholic population[67]. On this basis alone PAN is vastly superior to any BZ[39]. A number of workers have stated unequivocally that there is no evidence that one BZ is superior to any other[60,62,64,82]. The work involving oxazepam[77] and lorazepam[76], would seem to underline this. Guthrie also disagrees with the contention that short-acting BZ are superior by stating that “That there is no convincing evidence that these agents are better tolerated than those with a long half-life …”

Using a BZ regime produces another difficulty, also not associated with the use of PAN. BZ regimens do not allow the therapist to maximize the placebo response. Numerous workers consider the placebo response to be important in the therapy of the AWS, leading in many cases to recovery without pharmacological intervention[2,10,12-14,60,62,75,86] Some workers have stated that the use of BZ should be withheld for at least 4 hours after admission. This would enable supportive treatment, namely social detoxification programs, to be used before embarking on BZ treatment[87]. The use of placebo may avoid the sedation and cognitive impairment,associated with BZ therapy and which may retard early efforts at rehabilitation[62].

No treatment currently favoured in the USA, including any BZ regimen, is able to reliably and safely differentiate those patients who can safely be treated on an out-patient from those requiring in-patient therapy[82,88]. According to the latter workers “…we lack a solid a priori criteria….”[82] However, the advent of the PAN method changes this and provides a cogent reason for further investigations into the efficacy of the PAN therapy or any therapy that provides such criteria. This material clearly indicates that any BZ regime is best avoided if possible. It also emphasizes the importance of investigating and trying alternative approaches a notion supported by an editorial in the New England Journal of Medicine[89]. Here it was stated “Although the benzodiazepines remain the most commonly used agents for the management..” of AWS “..investigation of other agents is warranted because they “…may prove to have greater specificity.” Clearly, these options need not necessarily be superior to the BZs in controlling the AWS. Any simply applied treatment, having equal or better efficacy, without the side effects of the BZ, would be a considerable advance. Much evidence indicates that the PAN therapy for the AWS is such an improvement[1-20,20a].

The objectives of treating the AWS include relief of discomfort or treatment complications and speedy preparation for rehabilitation and the need to minimise adverse consequences of therapy, including drug dependency or toxicity[60,75] . Using these criteria there is no BZ regime which comes close to satisfying these requirements.

It would seem that any regime that :

• is more rational.
• is safer.
• the dose is easier to control.
• has fewer side-effects.
• is more rapid.
• maximizes the placebo response.
• is orders of magnitude less addictive.
• diminishes the reinforcing effect of oral and injection therapy.
• is simple (after a brief on-hands training period).
• provides a rapid screening test; dividing those requiring in-patient therapy from those that do not.
• is preferred by nursing staff and patients.
• is more economic; comes much closer to the ideal agent for treating the AWS.

On all these criteria the PAN therapy seems better than any BZ regimem[1-20,20a]. It therefore appears that despite their widespread acceptance as the gold standard treatment, there are definite problems associated with the use of BZ, which are reaadily overcome with the PAN approach.

Evidence is presented demonstrating that the PAN therapy has decided advantages over any currently available BZ regime.

SCIENTIFIC STUDIES OF PAN FOR AWS

Background

SABRI investigators have researched the effects of PAN on pain and pleasure states[8] in human subjects and thought it appropriate therefore, to investigate its effects on addiction. Initially the AWS was chosen. It soon became apparent that the administration of PAN, in the majority of cases studied, caused rapid and safe relief of symptoms. This amelioration occurring during the first hour of the administration; with lasting beneficial effect in over 90% of cases, such that further medication was restricted to low dose night sedation for one or at most two nights. Of the 5-10% not improving adequately after the first administration the majority responded to a second administration within the first 24 hours. It must be noted that SABRI restricted its investigations to mild and moderate cases of AWS.

Initially, to control for the effects of the PAN, 100% oxygen was given prior to PAN. In this sample a 60% plus positive response to oxygen on its own was observed. Clearly, this was not double-blind[2].

In all probability this work, would have stopped. However, the extremely positive input from the nursing staff at the Rand Aid Facility for alcoholic rehabilitation provided the impetus for it to continue. Both the matron and senior nurses of the latter facility indicated, in no uncertain terms, that in all their many years of specialist experience in treating AWS they had never come across so rapid, safe and effective a treatment of AWS. In particular, they were most impressed that the patients were not at all sedated by this treatment, as was the case where current sedative BZ methods of treatment were employed. A lack of sedation that enabled patients to rapidly abandon the sick role, as was exemplified by their ability to enjoy the next ward meal. They were also able to participate in the rehabilitation process from the very first day of admission. The staff also noticed that there was no rebound of symptoms despite the rapidity of the treatment. In the vast majority of cases, one administration of PAN was adequate to achieve rapid recovery.

It must be emphasized that until somebody has actually seen the rapidity of this therapeutic effect it is difficult to believe that such a expeditious and sustained improvement is possible in AWS.

In the large cohort of patients that has been treated with PAN the rapid anti-depressant, anti-craving, anxiolytic and other positive effects of the PAN on the AWS have been a feature of the method. It appears that these effects may be mediated by the opioid effects of PAN. Despite its short-acting partial agonist opioid properties, the positive effects of the PAN have almost always persisted for the full 7 days of in-patient detoxification, in most cases, after only one administration. In the rare cases where they have reappeared a second administration has eliminated them with lasting effect, with no reappearance during the 7 day period of detoxification.

It is therefore of interest that the South African Medical Research Council (MRC) delegation that visited SABRI in 1987 were extremely impressed by their interviews of patients that had received the PAN for AWS. They decided there and then to support further scientific work by ourselves in this area. This delegation consisted of 7 high ranking MRC appointed scientists including the then President Professor A. Brink.

The next problem arose as a result of the positive response to oxygen alone. It was therefore important to determine the extent and degree of the placebo response responsible for the improvement. This would enable the relative importance of the PAN in the therapeutic outcome to be assigned.

The first study to deal with the problem was published as a thesis, which was accepted in partial fulfillment for a Masters degree in clinical psychology by RAU (Rand Afrikaans University) in 1983[90]. In this study, which was single-blind, the experimenter did not know whether the patients had received gas or sedative medication on admission. However the nursing staff and the patients were aware of the treatment given, since no attempt was made to disguise this.

The patients were assessed over a 7 day period; on days 1; 4 and 7. The questionnaires used were the Nowlis Mood Adjective Check List and State Anxiety Inventory. Rating scales employed were the Brief Outpatient Psychopathology Scale; Psychotic Inpatient Profile; Nurses’ Observation Scale for Inpatient Evaluation. De Rooster concluded that there was no significant difference in the degree of improvement achieved by either treatments. But, importantly, he noticed that the side-effects of those treated with the BZ were greater than those found with the PAN. In particular the degree of sedation required to overcome the symptoms of the AWS, including insomnia, were far greater than were that required in the PAN group. In addition the PAN patients were much less obtunded than the control group, throughout the detoxification period. Since De Rooster[90] was not present during the administration of the drugs or PAN he was not able to comment on the very rapid alleviation of the condition by a single administration of PAN. He therefore did not compare the rapidity of action of the treatments.

The next step in distinguishing the differences between the BZ and PAN withdrawal treatments was to investigate further the degree of reduction of night sedation in the PAN group as compared to those treated with BZ. A single-blind approach was applied and the results showed a 79% reduction in sedation requirements of the patients treated with the PAN over the 7 day detoxification period. For the majority of cases the only sedation required was oxazepam on the first 2 nights following admission. It was also found that those treated with PAN were ready for discharge from the detoxification centre much earlier than the control group who had received sedatives alone[9]. Since then, the nursing staff have reduced sedative medication use by 75%- 95%[39].

A further study looked at the placebo effect and its contribution to the rapid therapeutic outcome. Here, 100% oxygen was compared double-blind against medical air. No significant differences was found between the 2 gases. The conclusion was that the positive effects of oxygen in the first study[2] could be ascribed purely to a placebo response[12].

As mentioned in the previous section, one of the major advantages of the PAN therapy over BZ regimes is that the therapist is able to maximize the benefits of the placebo response for the patient. As a result between 30%-60% of patients suffering from mild to moderate AWS are so substantially improved after receiving placebo gas (oxygen or air) that they do not require either PAN or any other pharmacological treatment during their 7 day detoxification stay[1,2,11,12,14].

The next study attempted to discover how many of those patients who did not respond to placebo would have a positive outcome if given PAN immediately after cessation of placebo. A very significant improvement in the vast majority of patients given PAN, who had not responded positively to the placebo, was observed. Clearly, a major problem inherent in these studies is blinding them effectively because of the rapidity of the therapeutic response. To obviate the problem a statistical method was used. In doing the statistical analysis the results observed with PAN were compared with those expected had PAN only been active as a placebo. Using this as the statistical basis, PAN was found to be statistically significantly better than placebo at the 0.01level[13]. All the references to the above work above can be found in the review articles[11,91].

More recently PAN has been found to be significantly superior to placebo, despite a wide ranging difference in placebo responses[14].

Furthermore a postgraduate student in clinical psychology at The University of the Witwatersrand has further investigated the psychological aspects of the very rapid response of patients treated with PAN for AWS. The findings of this single-blind study[92] on a small sample of 16 subjects was that PAN was superior to the BZ regime on depression scores immediate after PAN (ie. at 60 minutes from baseline) and 24 hours later. Depression at these times was measured using the Beck Depression Inventory. PAN therapy controlled anxiety as well as BZs when measured at these times on the State Trait Anxiety Inventory.

Another postgraduate student in clinical psychology at The University of the Witwatersrand has completed a further study on the effects of PAN on the psychological aspects of the AWS[93]. This study also single-blind (n=32), concentrated on comparing the immediate effects of PAN and BZ 60 minutes from baseline. The therapeutic effects of PAN were superior to BZ on all scales tested. This study indicated the superiority of PAN on depression (BDI), anxiety (STAI) and psychomotor function (Quick Neurological Screening Test – QNST) after one hour. However the differences were only statistically significant for the QNST because of large intersubject variations. It is likely that a larger sample will show that the PAN is significantly better for anxiety and depression in agreement with others[1-20,92]. However there is no doubt whatsoever that the PAN therapy is at least as good as the BZ therapy. The lack of side effects and other major advantages associated with PAN compared to BZs clearly makes the gas regimen superior[1-20, 92,93].

At the First International Conference of the Society of Neuroscientists of Africa in Nairobi, Kenya 8-13 March 1993 papers were presented on the PAN treatment for addictive withdrawal. Daynes showed that PAN was effective in rapidly decreasing craving in 98% of patients during treatment for alcohol and cannabis withdrawal[94] on an in-patient basis. Ojutkangas demonstrated the efficacy of the PAN therapy on out-patients in Finland. He also showed drastic reductions of sedative medication requirements when PAN is used on out-patients, as well as the possibility of employing the anti-craving effects of PAN to prevent relapses[18]. These papers were published in the International Journal of Neuroscience (for detailed references see refs no’s 223-227 in ‘SABRI publications‘).

Over the years investigators have used various forms of single-blind techniques[1-20]. Despite this, our scientific peers, who have not used the therapy or observed patients receiving it, have remained unconvinced of the scientific validity of the findings of our colleagues and ourselves. They have criticised us on the basis that no double-blind randomised trial has been conducted[94a]. For this reason, after more than two decades of safe and successful use of the therapy (in over 25,000 cases), without significant side-effects [1-20] or sequelae [1-20] we have undertaken a randomised double-blind trial of PAN versus a BZ, in this case diazepam. In this study (n=23) the PAN was statistically better than the BZ (5mg diazepam) at 2 hours and beyond [20a]. Using the same protocol we have subsequently shown that PAN is statistically better than BZ (n=51) even when an additional dose of a BZ is administered the night before the gases (paper in preparation).

The advantages of PAN over BZ regimens are outlined in a paper by Myles[20] commenting on thousands of cases from the nursing standpoint. They are:

1. rapid relief of symptoms “within minutes”.
2. no danger of oversedation with trained therapists.
3. easier management of patients who become co-operative almost immediately and therefore enter rehabilitation much earlier.
4. stress on staff is reduced because there is less physical nursing.
5. non-responders to PAN (a small percentage) require intensive monitoring and sedative treatment to prevent progression to delirium tremens – it provides a rapid effective screening test.
6. very low addictive potential (much lower than BZ).
7. cost-effectiveness.

She emphasizes that the technique is simple and easily reproducible as long as the therapist, usually a state registered nurse, has received a short hands-on training.

Thus it can be seen that at all times SABRI investigators have been acutely aware of the necessity for providing scientifically based proof for their conclusions, and those of others, that PAN is the most rapidly effective and safe of the currently available therapies. It is also more cost-effective in terms of medication and staff requirements[19,20].

In view of the above advantages the PAN therapy is proving invaluable in private practice and at the following venues in South Africa:

1. Newcastle SANCA (South African National Council on Alcohol and Durg Abuse) (Kwa Zulu – Natal)
2. Lenasia SANCA (Gauteng)
3. Themba Centre SANCA (Kwa Zulu – Natal);
4. Vaal Triangle SANCA (Orange Free State);
5. Port Elizabeth SANCA (Eastern Cape);
6. Laudium SANCA (Gauteng)
7. Wedge Gardens (Gauteng, Rand Aid).

Furthermore a colleague from Finland came to South Africa in 1989 specifically to be trained in the PAN method. He has successfully treated well over 6,000 cases to date[18].

Postwithdrawal rehabilitation

All patients are entered into a full rehabilitation program at these various facilities as soon as they are physically and psychologically well enough to do so. A major benefit of using the PAN therapy is the finding that within an hour, the vast majority of patients are well enough to socialise, eat, abandon the sick role and are therefore able to enter the rehabilitation program from the first day of admission. This is in stark contrast to the majority of patients who receive a BZ regimen.

Gas Administration

Importance of On-Hands Training for Correct Technique

It is essential to receive a specialised practical training course before PAN can be administered in a safe and effective manner for treating addictive withdrawal states. It can only be effectively and safely used by trained physicians and/or registered nurses. Consequently, it would be redundant here, to give a detailed description of the method. Nevertheless it is essential to understand that this is not an anesthetic technique. The gas is applied in analgesic concentrations with the patient fully conscious and co-operative at all times. There is no impairment of vital reflexes.

For these reasons it is totally unnecessary to take the precautions usually associated with the administration of a general anesthetic. This distinction between anesthetic and PAN is crucial. Only at the relatively low concentrations, consistent with analgesia is PAN a specific opioid agonist10,11 and effective in ameliorating the AWS[1-20,20a]

In order to achieve optimal results it is important to individualize this treatment for every patient since the concentration of PAN required varies widely between cases11. It can range from as low as 10% to as high as 70%. In the very rare cases where 70% PAN is required, it has been found that the alcohol abuse has caused increased tolerance to the effects of PAN. As a result, even at this high concentration the patient is not in any way sedated or obtunded. Initially the subject is given 100% oxygen for 20 minutes (consistent with tidal volume, usually approximately 6L/min)to familiarize the patient with the routine.

Actual Technique

Although a very simple technique only registered nursing staff who have qualified from a comprehensive, exhaustive, 10 day hands- on training course are allowed to administer the PAN (physicians can be trained over 2 days). The crucial part of this training course is the correct establishment of the end-point at which the patient is relaxed but not excessively sedated. At all times the staff keep in verbal contact with the patient, who must be able to answer rationally and without hesitation. Between 1979-1981, when the technique was initially investigated, patients were told that euphoria, excessive sedation and/ or excitation might occur.

At the end-point the patient appears relaxed without any signs of sedation. The specific signs are readily elicited by a suitably trained operator by carefully questioning of the patient on his/her subjective feelings before each gas increment. The subjective signs plus those observed by the individual administering the gas give a readily assessed end-point. Because the titration is done very slowly, with expert monitoring of the patient, (an essential part of the technique) subtle changes in the patients degree of consciousness are easily determined. At the earliest sign that verbal contact is obtunded, even if only minimally, the trained operator will note such changes and reverse them rapidly by increasing the oxygen percentage slightly. Since excitation occurs only in a very obtunded and sedated subject, who has already manifested signs of euphoria, the point of excitation can be avoided at all times. It is SABRI’s experience that with correctly trained staff that excessive sedation and excitation does not occur since the end-point is well before the stage of excessive sedation, which has to occur before the next stage, excitation is possible[98]. Therefore excitation can only occur after the patient has been excessively sedated i.e. to a point very close to anaesthesia, which is also beyond euphoria and well beyond sedation[98] and considerably beyond the endpoint required for ameliorating the AWS.

The end-point dose of PAN varies from subject to subject and is dependent on careful titration of dose against clinical response. However, as with any treatment requiring titration, it is impossible to standardise. The dosage of PAN “must be determined by the requirements of the patient, psychological conditioning,…”[40]

Adequate training and experience therefore prevents the administration of doses that are excessive or inadequate. This should also apply to any other treatments of the AWS, particularly those employing loading doses of BZs[62,99].

Careful attention to the technique is absolutely essential to achieve maximum efficacy[11].

The comfort zone or end-point is easily established clinically if the patient is carefully monitored for the clinical signs and symptoms. These are readily observed provided the individual administering the gas has received a simple hands-on training course.

In an experience of training more than 100 health professionals on the PAN technique, SABRI has come to the conclusion that only those who have been specifically trained on the customized equipment, are capable of reliably and safely administering the gases for the treatment of addictive withdrawal states.

Once the effective dosage is achieved it is then continued until the total exposure to PAN reaches 20 min. It is important to emphasize that the hall mark of the rapid effect is that it can occur either during initial oxygen or PAN administration i.e. literally within minutes of and during gas inhalation. \

In order to prevent any possibility of diffusion hypoxia, and clear the PAN from the subject’s system, at least 5 minutes of 100% oxygen is given after PAN, to all patients, through a nasal catheter[11].

Minimal Potential Risk

The risks to the patients from PAN are minimal [21a,21b,21c,23a] but certainly much less than for the BZ therapy, which tends to produce considerably more side-effects than does the PAN.

There is some epidemiological evidence that exposure to chronic high pollutant levels of nitrous oxide increases the risks if staff work in unscavenged operatories for long hours[100-103]. These untoward effects may include hepatic, renal, increased abortion rate,and neurological problems in those directly exposed. Increased abortions in dentists and their wives have also been reported[100]. Chairside assistants also appear to have an increase of congenital abnormalities in children born to them[100]. Recently evidence has been presented that women dental assistants exposed to high levels of pollutant PAN have reduced fertility[103]. It must be emphasised that all these findings are based on epidemiological evidence only which is fraught with possible defects[103]. There is no evidence that this applies to individuals who do not work continually in very close proximity to the nasal mask, nor for those exposed for an hour or less per day. None of those administering the therapy, to date, are exposed to more than an hour per day. Nor is there ever any necessity to work in close proximity to the nasal mask.

For instance, at the Rand-Aid Facility it is extremely unusual for more than 2 patients to be treated by the same staff member per day. Since 1979 the maximum number of times PAN has been used in one week is 15 (total exposure time for a 7 day period of 300 minutes). In this unusually active week the 3 professional nurses gave the gas an average of 5 times. In most weeks 5 -10 administrations of PAN are given spread between 3 nurses. This is considerably less than the equivalent of one half day’s exposure incurred by a chairside assistant in a dentists office, where PAN is used routinely. In addition the room in which the gases are administered is well ventilated.

However, in the light of the findings of Rowland et al[103] and despite the extremely infrequent and limited exposures to PAN by professional staff, scavenging equipment should always be employed. This will reduce the exposure of staff to levels well below those which are currently recognized as safe[101,102,104].

The risks of abuse to PAN are extremely low[23,39,101] and certainly considerably lower than to BZ [23,39]. Nevertheless the gas and the administration equipment is kept under lock and key except during the short periods in which the PAN is used. Under normal, therapeutic non-trial circumstances when PAN is used.

Under normal, theraputic no-trail circumstances when PAN is used, recovery is so rapid that the subject can drive and operate machinery within 30 minutes of cessation of the PAN administration. Since, in each case oxygen is given for 5 minutes after the PAN the subject only need wait in the facility for a further 25 minutes.

 

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