The term PAN was initially introduced to avoid confusion when speaking to medical professionals, about its use in neuropsychiatry and dentistry (12). Most physicians, apart from obstetricians (22), seldom, if ever, use the low concentrations favored in dentistry. And for labor analgesia, 50% N₂O is mainly administered briefly, intermittently, and on demand only (22). Dentists use low titrated concentrations of the gas (i.e., PAN), as an anxiolytic, while the patient is conscious and fully co-operative (7, 8, 12, 13). Any fixed concentration of N₂O is discouraged in modern dentistry (7, 8, 12, 17). Confusion occurs, because other medical professionals including anaesthesiologists, usually know the gas as part of balanced anesthesia only. Further, few anaesthesiologists have regular experience of using N₂O for minimal sedation in conscious patients, apart from those who regularly use procedural sedation and analgesia (44). And then, N₂O is usually part of a cocktail of other agents.

The differences are subtle. But are of paramount importance for ethical and practical reasons. Thus, readers must clearly distinguish subanaesthetic N₂O and PAN, although both fall within Stage 1 Anesthesia. PAN lies within the first half of Stage 1, while a 50% concentration lies in the second half of Stage 1 (19). Indeed, in some N₂O-sensitive individuals 25% may also lie within the second half of Stage 1 (19). The difference is more relevant now, since the latest work, features the administration of relatively high concentrations of subanaesthetic N₂O (1–6, 13, 15, 16, 19), not consistent with PAN (7, 8, 17, 33).

Unlike PAN these relatively high concentrations are administered via a full face-mask i.e., a relatively closed system for 30 (2, 3) or 60 min (1, 4, 5, 15). [I]In addition, the goal concentration seems more important than patient comfort (1–6, 15). In contrast, and by definition, PAN implies titrating N₂O to the lowest levels through a relatively open system (nasal mask) to each subjects clinical comfort, while fully conscious (7, 8, 10–12, 17, 47). There is definitely no goal concentration. Rather, the goal is maximum patient comfort and anxiolysis (7, 8, 12). For psychiatry, excellent results are obtained after 20 min only (9–11, 47). As a result, there are fewer side-effects, which when they occur, are milder (7–11, 13, 17).

A crucial result of these difference is that while using a similar semi-closed circuit (1–5), ~30% of subjects become unconscious while breathing 35–45% N₂O (24–26). Indeed, unconsciousness results even if the gas is applied for less than an hour (13, 24, 25). Further, in those not anesthetised while on a semi-closed facial mask system; and inhaling for considerably shorter periods than 60 min (2, 3), individuals suffer unpleasant side-effects like nausea, vomiting etc. while inhaling <50% (1, 5, 13, 24, 25), or 25% (7, 8). In contrast, correctly applied PAN does not result in anesthesia (7, 8, 13, 17, 19), while other side-effects are milder and less frequent (7, 8, 13). This because, the optimum dosage is evaluated by the practitioner on a case by case basis.

Importantly, like procedural sedation and analgesia (44) the gas is titrated to a clinical state (not a predetermined goal concentration) thus, there is no actual or finite concentration, even in the same subject (25) when PAN is correctly used (7, 8, 12, 13, 17, 44). But, once again these concentrations are lower than 50% (20, 21), and fall within the first half of Stage 1 Anesthesia (19).

There is another basis for the rarity of anesthesia and other untoward side-effects with PAN. Simply, the concentrations of N₂O are always lower than a 50% (1, 4–6, 15) or 25% (15) fixed mixture administered through a strapped facial mask, because dental flowmeters use a semi-open nasal mask system (7, 8, 13, 14) Further, dental flowmeters ensure that the maximum concentration, as per the rotameters is 70% (7, 8). And typical dental nasal-mask systems (7, 8, 12, 17), produce concentrations of N₂O reaching the pharynx less than half than those shown on the rotameters (20, 21). With PAN, <1%, of subjects require rotameter setting of 70%, which is the maximum concentration possible with a dental flowmeter. Here, the actual alveolar concentration of N₂O is <35%, in O₂. In terms of these lower rotameter to pharyngeal concentrations, Malamed indicates that 91% of subjects given 22.5% N₂O or less will be adequately sedated (7). Consequently, any fixed concentration of 25% (15) or 50% (1–5, 15) will cause numerous individuals to be over-sedated (7), resulting in avoidable side effects (7, 8).

Obviously, for balanced anesthesia, these variable concentration effects when N₂O is used are of limited import. Here the goal endpoint is rapid unconsciousness and not consciousness. Thus, for anesthesia, virtually all subjective effects can be discounted. Of course, this presupposes that the patient has good intra-operative analgesia and there is an absence of awareness, as well as post-operative recall. Clearly, where the gas is used on conscious people their subjective responses are of paramount importance.

N₂O, like any pharmacological agent used in procedural sedation and analgesia, manifests a normal bell-shaped distribution curve (7, 8) reflecting the sensitivity of subjects to the agent (7, 8, 12, 19, 44), when given during consciousness (7, 8, 11, 17). And, the dose-response curve is of central importance when administering rapid onset and offset agents like N₂O to conscious subjects (7, 8, 12, 17, 19, 25, 26). Furthermore, the dose-response curve in any individual, can vary even from day to day, because it is state rather than trait dependant (25, 77).

Apart from dose response differences, there is another important distinction. The mechanisms underlying PAN differs from higher subanaesthetic concentrations. For instance, the analgesic properties of subanaesthetic N₂O and PAN are mediated mainly by the endogenous opioid and GABA-ergic system (10, 11, 29, 31, 32, 38, 39). In contrast, the anesthetic actions of the gas occur mainly through N-methyl-D-aspartate receptor (NMDAR) (29, 30). As we have seen, some patients may be inadvertently anesthetised, when using a fixed 50:50 mixtures of N₂O (7, 8, 13, 17, 24–26). Thus, the underlying mechanisms governing the consciously experienced psychotropic actions of N₂O, are different to those where pre-anesthesia or anesthesia supervene. Consequently, one can see how the antidepressant actions of N₂O could wrongly be attributed to the NMDAR blockade (1–5, 15, 27, 78). Indeed, the same error has been made regarding ketamine, which until recently (27, 28, 79), was purported to have been due to NMDARs (1–5, 42).

Although convenient, and superficially more scientific to use fixed concentrations of 25% (15) or 50% (1, 2, 4, 5, 15) N₂O in oxygen, it may be imprudent to generalize findings with these concentrations. Particularly, because of the higher concentrations delivered by a relatively closed system. A factor complicated by the varying sensitivity of patients to N₂O (7, 8, 17, 24–27). These variables are virtually eliminated where the concentration is correctly titrated to patient comfort levels (PAN) (11, 12, 17, 27) as compared to higher subanaesthetic goal concentrations (1–5, 15). Moreover, the mechanism involved underlying observations (1–5, 15) may also be questionable (27, 78), even where the operator chooses to titrate to a highish goal concentration (1, 5, 24, 27, 28, 78). For these reasons, the use of continuous-flow, fixed concentrations of 25% (15) or 50% N₂O (1–6, 15), are inappropriate (7, 8, 12, 13, 24–27, 77).

Almost all these unwanted side effects, particularly inadvertent unconsciousness and/or nausea and vomiting are avoided by using the correct dental technique (7, 8, 13, 17). Here, the gases are titrated to each subjects' unique requirements, always using a nasal (7–12, 17), rather than a full-face (1–5, 15) mask. To use the dental technique safely, effectively, and correctly, a short hands-on training (lasting a few hours), is essential (36, 37, 40, 41).

From the foregoing it should be clear, that those using a 25% or 50% goal gas concentration mixture (1–5, 15) for periods above a few minutes, must therefore accept that unpleasant side-effects, such as inadvertent anesthesia, nausea, vomiting and inappropriate affective changes as inevitable in some cases (1, 7, 8, 13, 24–26, 43). A fact borne out in two studies, where nausea and vomiting has already been noted in subjects breathing 50% N₂O (1, 5, 15). These problems are almost always avoided when N₂O is titrated to each subjects' requirements (7, 8, 11, 12, 17, 40), so that the subject is always conscious and co-operative. For these reasons, readers will understand the practical importance of distinguishing between subanaesthetic and psychotropic concentrations of N₂O.

In the 19th and early 20th Centuries, 100% (hypoxic) N₂O was used for anesthesia (13, 80) which was potentially fatal, (80) possibly producing some deaths. Although, since the 1st years of the last century it was abandoned in medicine and dentistry, the confusion exists today. After training dentists and physicians in the PAN technique over 40 years, I am regularly told by potential trainees or anesthetists that the technique is dangerous. These people invariably confuse PAN with using 100% N₂O for anesthesia. It would be a pity, if PAN wrongly fell into disrepute, because an untrained practitioner, using 25% or 50% N₂O goal concentrations plus a full-face mask, produced a fatal pulmonary aspiration (43).

Although deaths are unlikely even when used at 50% or 25% (with a relatively closed circuits), unpleasant affective and physical side-effects are unavoidable in a certain percentage of patients (7, 8, 13, 15, 17, 24–26, 43), including vomiting, nausea and others, as confirmed recently (1, 5, 6, 15).

As discussed in some detail above, these high subanesthetic concentrations can and do, produce unconsciousness, vomiting, nausea and other disagreeable effects (1, 5, 6, 13, 24–26). Until the single controlled double-blind study (15) is repeated by others, these studies show promise only. Nonetheless, they do support the earlier work showing that PAN is antidepressant (9, 10). Interestingly, the same American group have published 3 reviews (23, 42, 81), heavily favoring the NMDAR and practically ignoring the other neurotransmitter systems, notably the opioid system (27).

Sadly, even if more studies are undertaken and confirm the north American work (15), the possibility of using fixed concentrations of 50% N₂O in general psychiatric or medical practice are limited. Such studies are limited unless an anesthesthesiologist administers the gas and we accept that many subjects will be oversedated. The evidence mentioned above, also clearly indicates that a 25% fixed dose is also unsuitable. Nonetheless, the realization that N₂O 25% (15) is probably better than 50% (15) seems an advance, particularly if these researchers realize the advantages of the PAN titration technique and to begin to use it. However, at this stage, the authors (1, 4, 6, 15) are still using arbitrary dosage rather than a dose optimized to each specific patient's needs.