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Federal Register / Vol. 86, No. 51 / Thursday, March 18, 2021 / Proposed Rules
Consequently, the positive identification of the four fentanylrelated substances in law enforcement encounters indicates that these substances are being abused, and thus pose safety hazards to the health of users.
2. Scientific Evidence of the Drugs Pharmacological Effects, if Known:
Fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl are pharmacologically similar to other schedule I and schedule II muopioid receptor agonist substances. The abuse potential assessed by drug discriminative studies of fentanyl carbamate, ortho-fluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl show that these substances share discriminative stimulus effects similar to fentanyl and morphine. Similar to schedule I and II
opioid analgesics, these four substances bind to and activate the mu-opioid receptor. Additionally, behavioral studies in animals demonstrate these
four substances produce analgesic effects similar to fentanyl and morphine. Pre-treatment with naltrexone, an opioid antagonist, attenuated analgesic effect of these four substances, as well as fentanyl and morphine. These data indicate that the four substances are mu-opioid receptor agonists with effects on the central nervous system. Data from drug discrimination studies showed that these four substances share discriminative stimulus effects similar to those of morphine. Thus, it is concluded from in vitro and in vivo pharmacological studies that the effects of the four substances are similar to that of fentanyl and morphine and are mediated by mu-opioid receptor agonism.
3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance: Fentanyl carbamate, orthofluoroacryl fentanyl, ortho-fluoro isobutyryl fentanyl, and para-fluoro furanyl fentanyl are synthetic opioids of the 4-anilidopiperidine structural class,
which includes fentanyl. As defined in the February 6, 2018, temporary order, fentanyl-related substances include any substance not otherwise controlled in any schedule i.e., not included under any other Administration Controlled Substance Code Number that is structurally related to fentanyl by one or more of the following modifications:
A Replacement of the phenyl portion of the phenethyl group by any monocycle, whether or not further substituted in or on the monocycle;
B Substitution in or on the phenethyl group with alkyl, alkenyl, alkoxyl, hydroxyl, halo, haloalkyl, amino or nitro groups;
C Substitution in or on the piperidine ring with alkyl, alkenyl, alkoxyl, ester, ether, hydroxyl, halo, haloalkyl, amino or nitro groups;
D Replacement of the aniline ring with any aromatic monocycle whether or not further substituted in or on the aromatic monocycle; and/or E Replacement of the N-propionyl group by another acyl group.

Figure 1: Regions of the chemical structure offentanyl described in the definition of
According to the February 6, 2018, temporary scheduling order, the existence of a substance with any one, or any combination, of above-mentioned modifications see Figure 1 would meet the structural requirements of the definition of fentanyl-related substances. The present four substances fall within the definition of fentanylrelated substances by the following modifications:
1. Fentanyl carbamate: Replacement of the N-propionyl group by another acyl group meets definition for modification E;

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2. ortho-fluoroacryl fentanyl:
Substitution on the aniline ring and replacement of the N-propionyl group with another acyl group meets definition for modifications D and E;
3. ortho-fluoro isobutyryl fentanyl:
Substitution on the aniline ring and replacement of the N-propionyl group with another acyl group meets definition for modifications D and E;
4. para-fluoro furanyl fentanyl:
Substitution on the aniline ring and replacement of the N-propionyl group with another acyl group meets definition for modifications D and E.

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No study has been undertaken to evaluate the efficacy, toxicology, and safety of the four substances in humans.
It can be inferred from data obtained from animal studies that these four substances have sufficient distribution to the brain to produce depressant effects similar to that of other mu-opioid receptor agonists such as fentanyl. Data from in vitro receptor binding studies show that these four substances, similar to fentanyl, display high selectivity for the mu-opioid receptor over other opioid receptor subtypes.

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a fentanyl-related substance