Development of Non-Opioid Analgesics for Acute Pain

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

34355740dft.docx
05/04/26
Development of Non-
Opioid Analgesics for
Acute Pain
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted as follows:
Submit electronic comments to https://www.regulations.gov. Submit written comments to the
Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852. All comments should be identified with the docket number listed
in the notice of availability that published in the Federal Register.
For questions regarding this draft document, contact Division of Drug Information at
druginfo@fda.hhs.gov; 855-543-3784 or 301-796-3400.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2026
Clinical/Medical
Revision 1

Development of Non-
Opioid Analgesics for
Acute Pain
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2026
Clinical/Medical
Revision 1

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DEVELOPMENT OF NON-OPIOID ANALGESICS .................................................. 2
A. 	Non-Opioid Analgesic Product Development for Acute Pain .................................................... 2
1. General Considerations ................................................................................................................... 2
2. Trial Design ..................................................................................................................................... 3
3. Outcome Measures to Obtain an Acute Pain Analgesic Indication ................................................. 4
4. Safety Considerations–Clinical Trial Elements ............................................................................... 6
B. Potential Claims in Labeling for Non-Opioid Analgesic Products for Acute Pain That
Eliminate or Reduce Opioid Use and Data Needed to Support Those Claims ............................. 7
1. FDA Thinking Regarding Concept of “Opioid-Sparing” ................................................................ 7
2. Reductions in the Use of Opioid Analgesics That May Merit Description in Labeling ................... 7
a. 	Product eliminates patient use of opioid analgesics ................................................................. 7
b. 	Product enables patient discharge without opioid analgesics ................................................... 8
c. 	Product reduces patient exposure to opioid analgesics with direct clinical benefit to the
patient............................................................................................................................................... 8
3. Data to Support Language in Labeling Describing Clinically Meaningful Reductions in Opioid
Analgesic Use................................................................................................................................... 8
C. 	Expedited Programs ...................................................................................................................... 9

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Development of Non-Opioid Analgesics for Acute Pain	1
Guidance for Industry1
2
3
4
5
6
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	7
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	8
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	9
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	10
for this guidance as listed on the title page.	11
12
13
14
15
I. 	INTRODUCTION	16
17
This guidance is written in response to the statutory requirements of section 3001(b) of the	18
Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT)	19
for Patients and Communities Act, which directs the Food and Drug Administration (FDA) to	20
issue or update existing guidance to help address challenges to developing nonaddictive medical	21
products to manage pain. In keeping with the mandate of section 3001(b), and considering the	22
severity of the ongoing opioid crisis, this guidance is also intended to assist sponsors in the	23
development of alternatives to opioids for the management of acute pain. Accordingly, this	24
guidance addresses FDA’s current thinking about three specific topics: development of non-	25
opioid analgesic products for acute pain, labeling claims, and expedited programs as they pertain	26
to this purpose.	27
28
This guidance does not address the management of chronic pain, which will be the focus of a	29
future guidance. This guidance also does not address the development of opioid products.	30
31
The contents of this document do not have the force and effect of law and are not meant to bind	32
the public in any way, unless specifically incorporated into a contract. This document is	33
intended only to provide clarity to the public regarding existing requirements under the law.	34
FDA guidance documents, including this guidance, should be viewed only as recommendations,	35
unless specific regulatory or statutory requirements are cited. The use of the word should in	36
Agency guidances means that something is suggested or recommended, but not required.	37
38
39
1 This guidance has been prepared by the Division of Anesthesiology, Addiction Medicine, and Pain Medicine in the
Center for Drug Evaluation and Research at the Food and Drug Administration. You may submit comments on this
guidance at any time. Submit comments to Docket No. FDA-2021-N-0556 (available at
https://www.regulations.gov/docket?D=FDA-2021-N-0556). See the instructions in that docket for submitting
comments on this and other Level 2 guidances.

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II. 	BACKGROUND	40
41
FDA is committed to using its authorities to take measures targeted to combat the opioid crisis.	42
In 2017, FDA announced its intention to focus on four priorities, two of which directly relate to	43
this guidance: (1) fostering the development of novel analgesic drugs and (2) decreasing opioid	44
analgesic exposure and preventing new addiction.2 To address these two priorities, and	45
consistent with our mandate under SUPPORT Act section 3001(b) to issue guidance in this area,	46
FDA is publishing this guidance.	47
48
For context, it is important to set forth FDA’s general understanding of pain and specific	49
definition of acute pain. For the purposes of this guidance, acute pain is defined as pain, lasting	50
up to 30 days, typically in response to some form of tissue injury, such as trauma or surgery.3	
51
52
This understanding informs the development of this guidance, which describes FDA’s current	53
thinking about three aspects of non-opioid analgesic drug development:	54
55
• 	The drug development program appropriate for a non-opioid analgesic to support an	56
indication for the management of acute pain (“acute pain indication”)	57
58
• 	The availability of claims in labeling of non-opioid analgesic products for acute pain	59
regarding elimination or reduction of opioid use and the data needed to support those	60
claims	61
62
• 	The use of expedited programs to support the development program for non-opioid	63
analgesics to manage acute pain	64
65
66
III. 	DEVELOPMENT OF NON-OPIOID ANALGESICS	67
68
A. 	Non-Opioid Analgesic Product Development for Acute Pain	69
70
1. 	General Considerations	71
72
Indications for analgesics intended to manage acute pain can be general or specific. A general	73
acute pain indication would reflect the expectation that the product will be effective for most	74
types of acute pain.4 The number of adequate and well-controlled clinical trials needed to	75
support a general acute pain indication depends on the mechanism of action of the drug, the	76
2 See the Opioid Policy Steering Committee web page, available at https://www.fda.gov/about-fda/office-medical-
products-and-tobacco/opioid-policy-steering-committee.
3 This definition of acute pain is consistent with the International Association for the Study of Pain’s definition,
which is as follows: “Acute Pain is generally accepted as being of recent onset and limited short duration. It usually
has a temporal (follows immediately after surgery/trauma) and causal (has a known cause) relationship to injury or
disease. The intensity of acute pain is greatest at the onset of injury, but with healing pain intensity reduces.”
4 Because of interindividual differences, a product indicated for general acute pain, and expected to be appropriate to
manage many kinds of acute pain, does not mean the product is expected to be effective for every patient.

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populations studied, and the degree to which the available information would support the	77
efficacy across the acute pain settings in which the product would be used. Products with well-	78
established analgesic mechanisms of action may be able to obtain a general acute pain indication	79
when supported by at least two clinical trials, each in a different pain population. For example, a	80
novel nonsteroidal anti-inflammatory drug with two successful clinical trials in postoperative	81
pain, one following bunionectomy and one following herniorrhaphy, may be suitable for a	82
general acute pain indication. In contrast, products with novel mechanisms of action are likely to	83
require clinical trials in more than two different pain populations to support a general acute pain	84
indication. As it is generally not feasible to study all possible populations that fall within a	85
general acute pain indication, it may be necessary to include language in labeling describing the	86
limitations of the indication.	87
88
A specific acute pain indication reflects results from studies in a specific pain population (e.g.,	89
postsurgical analgesia following hernia repair). Some products may be suitable only for specific	90
populations (e.g., topical analgesic for underlying soft tissue injury). A specific pain-type	91
indication generally requires evidence from at least two adequate and well-controlled clinical	92
trials.	93
94
Some sponsors may initially choose to demonstrate effectiveness of a particular drug in a	95
specific pain-type population and then subsequently pursue additional specific indications, or a	96
general indication, with additional trials in other acute pain settings to support broader use. In	97
both of these scenarios, additional patient populations and types of pain can be studied and study	98
results submitted as efficacy supplements to broaden the indication. In many cases, for both	99
additional specific indications or to expand the indication from a specific pain indication to a	100
general indication, one additional adequate and well-controlled efficacy trial may be sufficient.	101
102
2. 	Trial Design	103
104
Clinical trials to support a finding of efficacy for a non-opioid analgesic should be randomized,	105
double-blind, superiority trials. The trials should include repeat-dose design as appropriate.	106
Treatment duration should be based on the pain model used to support the proposed indication	107
sought but should be no fewer than 24 hours for products that are not limited to a single dose.	108
The primary endpoint should be based on the change in pain intensity over a suitable time period	109
based on the pain model used in the trial and the product’s expected duration of pain relief;	110
however, the time period assessed does not have to be for the full duration of the pain. After	111
evaluation of the primary endpoint, we recommend continued evaluation of both safety and	112
efficacy, for evidence of sustained effect, which may be relevant to acute pain lasting up to 30	113
days.	114
115
For acute pain, it is common to use an analysis such as the Sum of Pain Intensity Difference	116
(SPID) over a prespecified time period that reflects the expected duration of treatment effect of	117
the product. Demonstrating superiority to a comparator is important in non-opioid analgesic	118
trials because the primary endpoint, pain intensity, can be influenced by study design factors	119
such as the use of rescue medication and placebo effect. As a result, a noninferiority trial	120
showing no difference between analgesic treatments could mean that neither product worked in	121

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that study.5 Suitable comparators for the superiority study could include placebo or another	122
analgesic if the new product is expected to be more effective than the comparator analgesic. In	123
some cases, the test treatment and control (placebo or a different analgesic drug) may also be	124
added to background therapy (an “add-on study”). The background therapy could be specified or	125
caregiver selected.	126
127
Protocols should prespecify allowed rescue medications. Depending on the pain condition being	128
studied, rescue medications might include nonsteroidal anti-inflammatory drugs or, in clinical	129
settings in which opioids are typically required for adequate pain relief, opioids may be	130
considered. Protocols should also prespecify the frequency, amount, and threshold of pain at	131
which allowable rescue medication(s) can be administered. This is particularly important in	132
placebo-controlled trials where increased use of rescue medication in the control group may	133
diminish the study drug’s treatment effect, leading to a conclusion of ineffectiveness. The	134
statistical analysis plan should describe how discontinuations caused by inadequate pain control	135
will be handled. The concept of rescue use, including the prospective plan in the effectiveness	136
analysis to assess its use, as well as how the data support the overall indication, is important and	137
is discussed further in section III. A. 3. below, under Secondary Efficacy Endpoints.	138
139
3. 	Outcome Measures to Obtain an Acute Pain Analgesic Indication	140
141
Primary Efficacy Endpoint	142
143
In general, an assessment of pain intensity is the primary outcome measure to establish the	144
efficacy of an analgesic intended to manage acute pain. Efficacy endpoints (e.g., change in pain	145
intensity) in a non-opioid analgesic trial should reflect a direct rating of pain intensity by the	146
subject for all settings in which the subject can communicate in a reliable manner. We	147
recommend using a well-defined and reliable patient-reported outcome measure of the subject’s	148
pain intensity.6 The selected instrument should have the subject assess their pain at the time of	149
the assessment (i.e., without using a recall period). Generally, a numerical rating scale is the	150
appropriate measure.	151
152
We recommend that sponsors take frequent pain intensity measurements at preselected time	153
points during the trial to accurately measure the effect of a non-opioid analgesic and that effect	154
over time (e.g., every hour for X number of hours, then every 4 hours for X number of hours).	155
All pain intensity measurements, including at baseline, should be obtained before rescue drug	156
administration. In general, the frequency of pain intensity assessment is greater with initial drug	157
administration, early post-event (e.g., post-injury or surgery), when pain may be more intense.	158
The primary efficacy analysis should compare the SPID between treatments at a prespecified	159
time point that, at a minimum, includes the duration of drug effect, and may extend beyond this	160
5 See 21 CFR 314.126(b)(2)(iv) (providing “Similarity of test drug and active control can mean either that both
drugs were effective or that neither was effective.”) For more information about noninferiority trials, see the
guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016). We update
guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
6 For a thorough discussion of patient-reported outcome measures, see the guidance for industry Patient-Reported
Outcome Measures: Use in Medical Product Development to Support Labeling Claims (December 2009).

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duration. For example, a non-opioid analgesic with an expected 4- to 6-hour duration of action	161
might have the primary efficacy analysis performed at 24 hours post-dose (SPID24 ), but	162
secondary efficacy analyses may also be performed at 6 and 12 hours post dose (SPID6 and	163
SPID12 , respectively) to evaluate pain control during the recommended dosing interval.	164
165
We discourage using a primary endpoint that is based on pain relief (i.e., decrease in pain) rather	166
than pain intensity (i.e., how bad the pain is), as pain relief scales require subjects to report	167
current pain relative to their prior pain experience and may be influenced by other factors such as	168
concurrent adverse reactions, and may be limited by patients’ ability to recall their prior	169
experience of pain. Additionally, sponsors should generally avoid using composite scales that	170
are composed of multiple domains (e.g., pain, function, sleep) as the primary outcome measure	171
in a non-opioid analgesic trial. Such multiple domain scales may be difficult to interpret across a	172
population, as the same change in overall score can be based on differing patterns of response to	173
the individual domain scores. For example, an overall score may be higher at baseline, reflecting	174
poor sleep (with functional consequences), with improvement in the score reflecting	175
improvement in sleep, such as might be seen with a sedating drug that does not provide	176
substantive pain control. Multi-item scales, where the items all relate to pain (e.g., pain at rest or	177
with movement), may be useful depending on the type of pain being studied.	178
179
Secondary Efficacy Endpoints	180
181
Secondary outcome measures are important to fully characterize the efficacy of a non-opioid	182
analgesic and should support the primary efficacy endpoint. These secondary outcome measures	183
include measurement of time to onset of pain relief and time to rescue or request for next dose of	184
the study drug. Other informative secondary outcome measures include assessment of use of	185
rescue medications, physical function, and patient global impression of change of pain.	186
187
To measure time to onset of pain relief, FDA has accepted the “two stopwatch method.” In this	188
method, patients are instructed to stop the first stopwatch when they first perceive any analgesic	189
effect and instructed to stop the second stopwatch when they perceive a meaningful amount of	190
analgesia, which may be translated into a description in labeling of median time to meaningful	191
pain relief. FDA remains open to discussion and consideration of approaches beyond the “two	192
stopwatch method” to assess the time to onset of pain relief, which is particularly important to	193
establish if there is an expectation of rapid onset of action (e.g., intravenous formulation).	194
195
For all acute pain non-opioid analgesic studies, it is particularly important that sponsors record	196
the following information:	197
198
• 	The type and amount of rescue medication used, including dose, frequency, and duration	199
200
• 	The time that the study drug or rescue medication was administered	201
202
• 	The pain intensity measurements before the rescue medication was used and throughout	203
the dosing interval (e.g., evaluating SPID over the course of expected duration of action)	204
205

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Use of rescue medication can inform important properties of the drug and should be carefully	206
considered in the design of the study so as not to jeopardize the validity of the study. A sooner-	207
than-expected first use of rescue medication may suggest that the investigational drug has a	208
delayed onset of pain relief. Time to second use of rescue medication may be informative when	209
considering dosing interval for the investigational drug and supplement knowledge of the drug’s	210
pharmacokinetic properties. If the time to second use of rescue medication is earlier than	211
expected based upon drug exposure, waning efficacy can be considered a potential issue.	212
213
Endpoints Associated with Reducing or Eliminating Opioid Use	214
215
As discussed further below, total elimination of opioid or a numerical reduction in the number of	216
doses, dose per day, or duration of opioid use may support the efficacy of the investigational	217
drug in alleviating pain. In order to support a clinical benefit of a reduction in opioid use that	218
would be described in labeling, sponsors should demonstrate a direct patient benefit, such as	219
clinically meaningful reduction in the incidence and/or severity of opioid-induced adverse	220
reactions. See section III. B. below.	221
222
Biomarkers	223
224
FDA is not aware of any biomarkers that are useful in developing pain management products,	225
but we welcome feedback on this issue. If sponsors identify a way to use biomarkers in any	226
aspect of a clinical trial associated with non-opioid analgesics for acute pain, we are interested in	227
engaging on this topic.	228
229
4. 	Safety Considerations–Clinical Trial Elements	230
231
When monitoring safety during clinical trials, sponsors should consider the nature of the drug	232
and the trial population. Sponsors may also need to include subject discontinuation and/or study	233
stopping criteria in protocols, depending on the expected safety profile of a non-opioid analgesic.	234
235
Appropriate assessment of both effectiveness and safety relies on accurate and complete capture	236
of the reason for subject discontinuation. Sponsors should assure that when a subject	237
discontinues study drug or withdraws from the trial that the specific reason is obtained.	238
Investigators should be prompted to provide detailed information, with specific causes rather	239
than report terms such as “other,” “subject request,” “investigator decision,” or other such	240
nonspecific categories. Sponsors also should ensure that case report forms are designed to	241
accurately capture the reason for patient discontinuation.	242
243
The size of the safety database needed to support approval for an acute pain indication depends	244
on a number of factors, including whether the drug is a new molecular entity or a reformulation	245
of an approved drug substance. In addition, a nonclinical safety finding or safety data from early	246
clinical studies suggesting a potential serious adverse reaction may necessitate enlargement of	247
the safety database to better define the safety profile of the proposed product. Safety	248
assessments should continue as appropriate after dosing is completed, with consideration of	249
patient population and setting (i.e., inpatient versus outpatient).	250
251

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Early in development, sponsors should discuss safety considerations, including the safety	252
database requirements, with FDA.	253
254
B. 	Potential Claims in Labeling for Non-Opioid Analgesic Products for Acute	255
Pain That Eliminate or Reduce Opioid Use and Data Needed to Support	256
Those Claims	257
258
1. 	FDA Thinking Regarding Concept of “Opioid-Sparing”	259
260
Consistent with the feedback of the Anesthetic and Analgesic Drug Products Advisory	261
Committee on November 15, 2018, FDA believes the term “opioid-sparing” as a statement in	262
labeling is unlikely to be sufficiently descriptive to be meaningful. Instead, FDA recommends	263
labeling that more clearly and specifically explains the benefits provided by eliminating or	264
reducing the need for opioid analgesics as discussed in section III. B. 2. below.7 For drugs that	265
are already approved and for those that are seeking initial approval, considerations in describing	266
elimination or reduction in the need for opioid analgesics are similar.	267
268
2. 	Reductions in the Use of Opioid Analgesics That May Merit Description in	269
Labeling	270
271
There are several ways in which a non-opioid analgesic may show benefit in reducing opioid use	272
that would merit description in labeling:	273
274
• 	Eliminating patient use of opioid analgesics in some or all patients in a pain setting in	275
which use of opioids would typically be required to alleviate pain	276
277
• 	Providing adequate analgesia such that the patient can be discharged from the health care	278
facility without opioid analgesics when patients would be expected to be discharged with	279
opioid analgesics	280
281
• 	Showing a direct patient benefit related to reduced opioid analgesic use, such as a	282
clinically meaningful reduction in opioid-associated adverse reactions or earlier	283
functional recovery (e.g., earlier ability to participate in physical therapy with earlier	284
regain of ambulation)	285
286
In each of these scenarios, data should support a finding that the non-opioid and opioid have	287
comparable effects on pain.	288
289
a. 	Product eliminates patient use of opioid analgesics	290
291
Exposure to an opioid analgesic presents a risk of addiction, misuse, or abuse. In addition to the	292
risk of addiction, opioid use also may cause serious adverse reactions, including overdose, and	293
death. Therefore, a non-opioid analgesic for acute pain that completely eliminates the need for	294
7 This view is consistent with feedback provided at the November 15, 2018, Meeting of the Anesthetic and
Analgesic Drug Products Advisory Committee. See https://www.fda.gov/advisory-committees/advisory-committee-
calendar/november-15-2018-meeting-anesthetic-and-analgesic-drug-products-advisory-committee-meeting.

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an opioid in a setting in which opioid-level analgesic would be otherwise necessary would have	295
the greatest impact on reducing the risk of opioid addiction. In addition to reducing the risk for	296
the patient, the absence of opioid analgesics in the home lessens access to others in the same	297
residence who may seek opioid analgesics for misuse or abuse.	298
299
If a sponsor can show that a product eliminates the need for an opioid analgesic in a statistically	300
significant number of patients in a setting in which opioids are routinely required for adequate	301
acute pain control, this finding could be sufficient to support description in labeling. In such	302
circumstances, labeling that describes analgesia comparable to or better than the comparator	303
opioid may be appropriate.	304
305
b. 	Product enables patient discharge without opioid analgesics	306
307
As with products that eliminate opioid use, if a sponsor demonstrates that a non-opioid analgesic	308
product eliminates the need for an opioid to manage acute pain at discharge from a health care	309
facility or other outpatient settings, when opioid use post-discharge is routinely needed, this also	310
could be considered adequate to support description in labeling. Additional assessments after	311
discharge would be required to confirm patients’ pain can be managed without opioids.	312
Reducing the supply of prescription opioid analgesics in the home reduces the risks of misuse	313
and abuse by both the patient and others within the home. Labeling that describes these findings	314
may be appropriate.	315
316
c. 	Product reduces patient exposure to opioid analgesics with direct clinical	317
benefit to the patient	318
319
Apart from discharge by a health care facility without opioids, reduction in dosage and/or	320
duration of opioid use alone is not likely to be adequate to support description in labeling. To	321
include a reduction in opioid use in labeling, the reduction claim should be associated with a	322
direct patient benefit such as (1) reduced time to recovery of function, such as more rapid	323
mobility and/or earlier ability to participate in rehabilitation or other clinically meaningful	324
functional outcomes, or (2) a relevant decrease in opioid-related adverse reactions such as less	325
sedation, fewer gastrointestinal side effects (such as constipation), or other adverse reactions. If	326
these types of clinical benefits are adequately demonstrated in clinical trials, language in the	327
labeling delineating these benefits could be included.	328
329
3. 	Data to Support Language in Labeling Describing Clinically Meaningful	330
Reductions in Opioid Analgesic Use	331
332
To support language describing clinically meaningful reductions in opioid analgesic use in	333
product labeling for any of the categories described above, sponsors should provide data from at	334
least two adequate and well-controlled trials. As described in section III. B. 2. above, examples	335
of clinically meaningful outcomes include not requiring opioids for a pain model where opioid	336
use is usually required, or, where use of opioids is still needed, showing reduced opioid dose	337
requirements in concert with either a shortening of time to mobility (e.g., following orthopedic	338
surgery) or a reduction in the frequency of major complications of opioid treatment, such as	339
delirium in an elderly population or a reduction in opioid-related adverse reactions.	340

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341
FDA also encourages sponsors to include open-label extensions with follow-up assessment of	342
opioid analgesic utilization (e.g., 30 days after discharge following a surgical procedure) to	343
assess whether patients have been taking opioid analgesics during the period of extension.	344
345
FDA does not recommend observational study designs or exclusive use of electronic health care	346
data (e.g., electronic health record or administrative claims data) to support labeling language	347
describing clinically meaningful reductions in opioid analgesic use. Electronic health care data	348
are not sufficiently able to measure factors that may drive selection of patients for the	349
investigational versus the control treatment. Likewise, routinely collected health care data (e.g.,	350
administrative claims data) are insufficient to ascertain primary endpoints, such as pain control,	351
level of function, actual opioid use, and adverse effects.	352
353
However, incorporating electronic health care data may be useful in other respects. For instance,	354
such data may be valuable (1) in assessing opioid analgesics dispensed at discharge and	355
persistent prescribed opioid analgesic dispensing, (2) in understanding current practices and	356
standards of pain management in specific clinical settings, and (3) in identifying patients who	357
may be eligible for study participation. We remain interested in feedback on ways in which	358
these data could be useful to support the development of non-opioid analgesic products.	359
360
We recognize that we are not addressing all aspects of clinical trial design for products that may	361
reduce the use of opioid analgesics in a way that may merit description in product labeling, and	362
we invite comment on this area of clinical trial design in response to this guidance. We also	363
encourage sponsors of any non-opioid analgesic for acute pain seeking a claim of opioid	364
replacement or reduction in labeling to have early and regular discussions with FDA to help	365
ensure the use of adequate and interpretable assessments of treatment benefits that are consistent	366
with a drug’s mechanism of action.	367
368
C. 	Expedited Programs	369
370
FDA encourages the development of non-opioid analgesic products and novel study designs.	371
Non-opioid analgesic development programs designed to replace or reduce the use of opioid	372
analgesics may be eligible for one or more of FDA’s expedited review programs, as applicable.	373
FDA encourages early discussion of products that could eliminate or reduce opioid analgesic use	374
and may be suitable for expedited reviews.	375
376
These expedited programs and their relevant criteria are described in the guidance for industry	377
Expedited Programs for Serious Conditions–Drugs and Biologics (May 2014). The applicable	378
expedited programs include fast track, breakthrough therapy, priority review, and accelerated	379
approval. Although each program differs, they all offer some form of expedited review and	380
guidance for sponsors for drug development programs.8	
381
8 In addition to the programs outlined above, the Breakthrough Devices Program may be available for certain
nonaddictive medical products to manage pain. (Federal Food, Drug, and Cosmetic Act § 515B (21 U.S.C. 360e-3)).
The Breakthrough Devices Program is a voluntary program for certain medical devices and device-led combination
products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating
diseases or conditions. The guidance for industry and Food and Drug Administration staff Breakthrough Devices

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FDA has not had experience with an analgesic approval based on a surrogate or intermediate	382
endpoint that is reasonably likely to predict clinical benefit, as would be consistent with	383
accelerated approval.9 Given that pain intensity is a subjective experience that can only be	384
directly reported by the patient, it is difficult to envision how surrogate or intermediate endpoints	385
could be used to predict analgesic effect. However, consistent with applicable statutory criteria,	386
FDA will consider a non-opioid analgesic’s abuse or misuse potential and its risk profile relative	387
to available opioid analgesics to determine if the application qualifies for fast track or	388
breakthrough designation during development, or for priority review upon receipt of the	389
marketing application.	390
Program (December 2018) outlines the criteria for designation as a breakthrough device as well as the policies FDA
intends to use to implement the program. The considerations set forth in that guidance document apply to FDA’s
review of devices as nonaddictive methods to manage pain.
9 See FD&C Act 506(c) and 21 CFR 314.500 et seq. For drugs granted accelerated approval, postmarketing trials
have been required to verify and describe clinical benefit.