Introduction

Bunionectomy is the most common acute postoperative pain model used in pain drug development programs geared at US and/or European regulatory approval (see Table 1 below). Since 2008, 12 drugs have been approved for acute pain (in either the US or EU). 10 out of 12 of these drugs utilized bunionectomy in their development programs (9 in Phase 3, and 1 exclusively in Phase 2) (Table 1).

Despite the prevalence and importance of the bunionectomy pain model, the authors are not aware of any existing review article or meta-analysis that specifically addresses the topic. As such, researchers who wish to utilize bunionectomy as an experimental model are forced to cobble together information from disparate sources. In this paper we will present a comprehensive table of bunionectomy acute pain studies performed or published in the past 15 years, identifying the key outcome measures and experimental features that were employed in each study. Additionally, we will provide an overview of the surgical, anesthetic, and perioperative analgesic techniques typical to a modern bunionectomy acute pain study. We will outline common design paradigms, inclusion/ exclusion criteria, assessments and endpoints, rescue medications, and other key clinical and operational details of bunionectomy trials.

Table 1 Postoperative Acute Pain Drug Approvals Since 2008 (US and/or EU)

Acute Postoperative Pain Models: Clinical Relevance vs Experimental Quality

Postoperative pain after bunionectomy can in most cases be treated adequately with existing therapies.13,14 In contrast, pain from larger and more complex hard tissue surgical procedures (eg, total knee arthroplasty, total hip arthroplasty, major spine surgeries, thoracotomies, etc.) is inadequately addressed by existing analgesic drugs.15 There is a clinical need to develop novel analgesics to treat pain generated by these larger surgeries. Therefore, clinicians reviewing data on novel analgesics would be best informed by data from studies performed in these larger models, where the study population’s pain syndrome most closely resembles that of the patient in need of new therapies. However, larger and more complicated surgical models can give rise to an increased chance of a false negative outcome as the assay sensitivity of experiments performed in these models is relatively low.16

Of the larger surgeries listed above, the most popular and well-understood choice as a clinical trial model is total knee arthroplasty (TKA).17 However, TKA is not frequently employed as a pivotal model for efficacy because it has certain characteristics that can negatively impact assay sensitivity,18 including the following:

Patients undergoing TKA have significant comorbidities that can necessitate modifications to protocol-mandated anesthetic and surgical procedures (giving rise to increased variability).19 Surgical and anesthetic capabilities (eg, robotic surgery, ultrasound-guided nerve blocks) differ significantly between hospitals. Multiple doctors and caregivers are involved with the perioperative care of TKA patients. The resultant increased number of clinical touch points with the study subject can increase variability and placebo response. Slower recruitment rates for TKA studies can result in the need to increase the number of study sites, which can erode assay sensitivity in pain studies.20

In contrast, bunionectomy is a relatively simple procedure typically performed on younger, healthier patients, and bunionectomy trials are often performed by actively recruiting patients into a small number of specialized surgery centers where care is highly standardized (see Recruited vs Non-Recruited Surgeries below). While the Dental Impaction Pain Model (DIPM, ie wisdom tooth extraction) offers similar benefits, it is no longer accepted by regulatory agencies as a pivotal model.18

The prevalence of bunionectomy in pivotal clinical trials represents a compromise. Studies in more clinically relevant models are more likely to fail, and so researchers who select bunionectomy trade off some clinical relevance of their study data for a lower likelihood of a Type 2 error.

Recruited vs Non-Recruited Surgeries

A key component of bunionectomy’s strength as a model for clinical experiments lies in its origins as an actively recruited study model. Prior to the development of bunionectomy, pivotal postoperative pain studies generally enrolled patients who were scheduled for surgery independently of the research project (the subject’s surgery was not predicated on study participation). Actively recruited models like bunionectomy introduced a new paradigm.18 Researchers recruit subjects through advertising and patient databases. Surgical costs are generally paid by the study sponsor, rather than by the subject or insurance. This paradigm allows researchers to enroll subjects quickly into a small number of research centers where surgery, anesthesia and perioperative care are strictly standardized and can be tailored to the needs of study protocols.21 Subjects can also be domiciled longer than typical clinical care standards would dictate (eg, a 72-hour inpatient stay for a bunionectomy), enabling:

Study assessments to be performed by study staff who are expert in analgesic assessments. Control and verification of investigational product and rescue medication administration. Control and verification of efficacy and safety assessment time points. Control of activities that would likely confound efficacy assessments (such as subject ambulation).Diagnosis

In an actively recruited surgical study model, fast, simple, unambiguous diagnosis of the underlying condition requiring surgery is key to rapid enrollment. Bunions requiring surgery of the type used in clinical trials (type 2 hallux valgus deformity) are relatively simple to diagnose.22 Generally, clinical presentation involves pain, difficulty with ambulation and improper fit of the shoe. A clinical examination and plain film X-ray are adequate for confirmation of the diagnosis in most cases.

Surgical Procedure

Postoperative pain after bunionectomy largely arises from the osteotomy (cutting of bone) required for the procedure, and to a lesser degree from the damage to surrounding soft tissues required for surgical exposure. Therefore, standardization of the surgical osteotomy is paramount to ensure experimental homogeneity.

The Austin/ Chevron bunionectomy procedure used in most bunionectomy pain trials is performed entirely on the first metatarsal head and provides correction for moderate Type 2 hallux valgus deformity. Subjects requiring alternate types of metatarsal head osteotomy, as well as base wedge osteotomies (in which the base of the first metatarsal is cut to correct severe deformities), are excluded. Collateral procedures, including hammertoe repair, are generally not allowed. Only subjects undergoing primary unilateral surgeries are included. Total length of convalescence is approximately 8 weeks or more postoperatively, with approximately 4 weeks spent in a surgical shoe.23

An illustrated outline of a typical Austin procedure is below (Figure 1):

Figure 1 Continued.

Figure 1 Illustration of Austin bunionectomy surgery. A video demonstration of the Austin procedure is available online: https://www.arthrex.com/resources/PAN1-00010-EN/first-metatarsal-distal-chevron-osteotomy-with-lps-screw.24 (A) Hallux valgus deformity of first metatarsal head. (B) An osteotomy is performed to remove the Prominent bump from the first metatarsal head. (C) A V-shaped osteotomy is performed on the first metatarsal head. (D) The first toe is shifted laterally, which corrects the deformity. (E) A screw or pin is placed to provide external fixation. (F) An osteotomy is performed to trim the remaining lateral bone fragment. (G) The result is a smooth edge on the first metatarsal head. These images provided courtesy of Arthrex, Inc.

Study Design Paradigms: Timing of First Study Treatment Dose

In bunionectomy studies, the most critical design consideration centers around the timing of the first dose of investigational product relative to the time of the surgery. There are 4 paradigms:

A. Preoperative Dosing First dose of study drug is given before surgery (study drug is administered prior to the patient entering the operating room). Since subjects are not yet experiencing postsurgical pain when the first dose is administered, a pre-dose baseline pain measurement will not be available for endpoint calculations. Preoperative designs therefore cannot use summed pain intensity difference (SPID) endpoints and must employ an area under the curve (AUC)/ summed pain intensity (SPI) methodology (see Endpoints). Speed of onset measures such as the 2-stopwatch technique cannot be employed.

A preoperative design is typically utilized when the IP has a delayed onset of action (>90-120 minutes). For example, for an oral drug that takes 4 hours to reach an efficacious blood level, one might administer the drug 2 hours prior to surgery. By the time the patient wakes up from anesthesia and is ready for postsurgical efficacy assessments, the drug is able to provide analgesic relief.

B. Intraoperative Dosing First dose of study drug is given during surgery (study drug is administered while the patient is under anesthesia and surgery is ongoing). Because the patient is heavily sedated, a baseline pain measurement cannot be provided. Intraoperative designs must employ an AUC/ SPI methodology (see Endpoints). Speed of onset measures such as the 2-stopwatch technique cannot be employed.

This paradigm is required for infiltration analgesics (drugs that are injected into an open surgical wound, such as local anesthetics and injectable capsaicin). It can also be used for intravenous analgesics administered while the subject is under anesthesia.

C. Postoperative Dosing, Day 0 First dose of study drug is administered on the day of surgery, approximately 1–4 hours postoperatively. Generally, subjects are pain free for about an hour after surgery secondary to the intraoperative Mayo block (see Mayo Block). The block will begin to wear off 1–4 hours after surgery. Subjects must report adequate pain for randomization postoperatively (see Postoperative Inclusion Criteria). The qualifying pain score is considered to be the subject’s baseline. A baseline pain score allows use of SPID as a primary endpoint (see Endpoints). Speed of onset measures such as the 2-stopwatch technique can be employed.

The immediate postoperative pain signal from bunionectomy is intense on the day of surgery. As such the Postoperative Day 0 design should only be used for drugs with high potency and rapid onset. It is important to match the pain trajectory of the experimental model to the characteristics of the investigational product (see Figure 2).

Figure 2 Matching experimental pain signal to study drug potency. Cooper (1983)25 compared designing an analgesic study to setting the height of an Olympic high jump bar. Assuming the study drug is efficacious, a study should be designed so the “bar” (pain intensity during the treatment period) is at the correct level where active drug can clear it but placebo cannot (B above). If the bar is too low (not enough pain A), both placebo and study drug will clear the bar, and the study will fail. If the bar is too high (too much pain C), neither study drug nor placebo can clear the bar, and the study will fail. To separate an efficacious treatment from placebo, one must design the study to tailor the expected pain signal with the expected potency and onset characteristics of the study drug.

D. Postoperative Dosing, Day 1 First dose of study drug is given the morning after the day of surgery. A popliteal catheter is inserted during surgery to continuously numb the foot (see Popliteal Block). On the morning after surgery, the catheter is removed and the numbness recedes.Subjects must then report adequate pain for randomization postoperatively (see Postoperative Inclusion Criteria). The qualifying pain score is considered to be the subject’s baseline pain. A baseline pain score allows use of SPID as a primary endpoint (see Endpoints). Speed of onset measures such as the 2-stopwatch technique can be employed.

The Postoperative Day 1 design is by far the most common in bunionectomy clinical trials (see Summary Table of Bunionectomy Acute Pain Clinical Trials). The use of a popliteal catheter on the day of surgery allows pain from the surgical insult to partially recede overnight, such that when the patient is ready for randomization on the day after surgery, their pain trajectory is not as severe as it would have been on the day of surgery. This pain signal is an appropriate match for intermediate potency oral analgesics (investigational agents with potency similar to ibuprofen, hydrocodone, or acetaminophen). See Figure 2 re: matching the experimental pain signal to the study drug.

Figure 3 provides a timeline of key events for each dosing approach.

Figure 3 Timelines for each dosing paradigm.

Sedation and Anesthesia

Anesthetic protocols can vary depending on the needs of a given study. One key asset of the bunionectomy model in clinical trials is the ability to adjust anesthesia and immediate postoperative analgesia to influence the onset and duration of a subject’s pain trajectory (see Popliteal Block for one example). From an experimental viewpoint, the ideal anesthetic regimen utilizes short-acting drugs that dissipate quickly and as such do not have carryover effects that would confound the efficacy evaluation period. The following anesthetic protocol is typical of modern bunionectomy studies:

Propofol at approximately 50–150 µg per kilogram per minute is titrated to achieve light sedation appropriate for monitored anesthesia care (MAC). 1–2 mg of midazolam may be given for preoperative sedation. Muscle relaxants are not used. Surgical anesthesia is generally achieved with a Mayo block (see Mayo Block below). 50–100 ug of fentanyl is allowed for intraoperative analgesia.Mayo Block

The Mayo block is a field block around the base of the first metatarsal.26 Local anesthetic is infiltrated proximal to the surgical site in a ring-type fashion. The block is performed after the patient is sedated but before surgery is initiated. The patient generally experiences dense anesthesia and near-complete numbness of the surgical area. The onset and duration of the block will vary depending on the local anesthetic employed (see Table 2). In bunionectomy trials, all subjects (regardless of the dosing paradigm) will receive a Mayo block. Subjects in Postoperative Dosing, Day 1 studies will also receive a popliteal block.

Table 2 Example Mayo Block Specifications

Popliteal Block

In Postoperative Day 1 studies (Paradigm D), a popliteal sciatic nerve catheter is placed in the popliteal fossa (the diamond-shaped space behind the knee joint) under ultrasound guidance. The catheter is used to infuse an intermediate-duration local anesthetic giving rise to a numb foot in most subjects.

Administration of local anesthetic for the popliteal block involves a loading dose followed by a continuous infusion and optional bolus doses. A variety of local anesthetics can be used. Examples of typical infusion protocols are presented in Table 3.

Table 3 Example Popliteal Block Specifications

Example popliteal block specifications can be found in Table 3. The popliteal block is typically removed early in the morning on the day after surgery (at/around 4am). Numbness in the foot recedes over the next 8 hours. When the patient develops adequate pain (see Postoperative Inclusion Criteria), they are randomized into the study and administered their first dose of study treatment.

Typical Inclusion/ Exclusion Criteria Preoperative Inclusion/ Exclusion (I/E) Criteria

Bunionectomy programs seek to enroll subjects who are:

Relatively healthy Appropriate candidates for surgery (unilateral Austin bunionectomy) and anesthesia Unlikely to be allergic or intolerant to the investigational product or the protocol-mandated rescue medications, and Likely to provide non-confounded analgesic assessments.

In order to achieve point 4, subjects are excluded if they (1) have additional underlying painful conditions beyond bunion pain or (2) are currently taking opioids (eg >15 mg hydrocodone on any single day in the 2 months prior to surgery and any opioid within 10 days of surgery).

Postoperative Inclusion Criteria

In addition to the I/E criteria performed at the screening visit, studies using a postoperative dosing paradigm must specify a set of postoperative criteria to be assessed after the subject wakes up from surgery and begins experiencing pain. Namely, subjects must report postoperative pain that is: A) moderate or severe on a 4-point categorical scale (none, mild, moderate, or severe) and B) ≥4 or 5 on an 11-point NPRS (see Efficacy Assessments).

Efficacy Assessments

The most common efficacy assessments used in bunionectomy studies are as follows:

NPRS

The numeric pain rating scale (NPRS) is an 11-point scale that requires the subject to select a whole number (between 0 and 10) that best reflects their current pain intensity. A 0 represents “no pain” and a 10 represents “the worst pain imaginable”.

Assessment schedules in bunionectomy studies typically call for a scheduled NPRS to be captured at the following time points (in hours): 0.25, 0.50, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and then every 4 hours until Hour 48 (or end of study). In addition to scheduled NPRS assessments captured at specified time points, unscheduled NPRS assessments are also recorded A) immediately prior to use of any analgesic rescue medication and B) prior to subject discontinuation if it occurs before the end of the treatment period. Unscheduled NPRS assessments allow imputation of data that is confounded due to rescue or missing due to early discontinuation.

VAS

The visual analog scale (VAS) is a 100 mm line that the subject is asked to mark in a location that best reflects their current pain intensity. Multiple studies have shown that the NPRS and VAS are comparable in regards to assay sensitivity.27,28 However, use of VAS in bunionectomy trials has largely fallen out of favor, due to complexities caused by errant marking of the diary by study subjects.

Patient Global Assessment of Pain Control (PGA)

The PGA is a 4- or 5-point scale that asks the subject to “rate how well your pain has been controlled since you received study medication” (there are varying versions with slightly different language). Allowed responses for the 5-point version are Poor, Fair, Good, Very Good or Excellent.

2-Stopwatch Assessments

Studies using postoperative dosing paradigms typically assess speed of onset using the 2-stopwatch technique. When a subject receives their initial dose of study drug, two stopwatches are simultaneously started. One stopwatch is labeled “Perceptible Relief” and the other is labeled “Meaningful Relief”. The study coordinator provides the Perceptible Relief stopwatch to the subject and places the Meaningful Relief stopwatch near the bedside.

The subject is instructed to press the Perceptible Relief stopwatch when they feel “any pain relief at all”. After the study subject achieves Perceptible Relief, the study coordinator provides the subject with the Meaningful Relief stopwatch. The subject is instructed to press the Meaningful Relief stopwatch when “they experience pain relief that is meaningful to them”.

Pain Relief Assessments

Assessments of pain relief (eg, TOTPAR) ask the subject to rate “how much pain relief they have had since the first dose of study medication”. Allowed responses are None, A Little, Some, A Lot and Complete. In multidose trials, pain relief assessments can confuse study subjects and as such they have not been included in most modern bunionectomy trials.

Rescue Medication

Time to first use of rescue, and amount of rescue used over various time intervals, are commonly recorded (see Measurement of Rescue Analgesics).

Endpoints Typical Primary endpoints SPID

Summed Pain Intensity Difference (SPID), used in Postoperative Dosing, Day 0 and Day 1 paradigms, is the most common primary endpoint utilized for bunionectomy studies. SPID measures how a subject’s pain intensity changes over time in relation to the baseline pain score assessed at randomization (Figure 4). Only subjects who are dosed after surgery (Postoperative Day 1 and Postoperative Day 0 designs) can record a baseline pain intensity, and therefore only postoperative dosing designs can utilize SPID as an endpoint. SPID is calculated utilizing a time-weighted average of NPRS scores.

Figure 4 Summed Pain Intensity Difference (SPID). A: Dotted black line represents the mean baseline pain intensity, against which future measurements will be compared. B: Blue line represents mean pain intensity reported by the placebo arm. C: Red line represents mean pain intensity reported by the active arm. D: Gray area represents treatment effect (mean active change from baseline – mean placebo change from baseline).

SPI (Auc)

Summed Pain Intensity (SPI), (often called Area under the Curve [AUC]) is utilized for Pre- and Intra-operative dosing paradigms. Like SPID, SPI is a time-weighted average of NPRS scores. However, because there is no baseline pain intensity, the active and placebo arms may have differing baseline values (Figure 5).

Figure 5 Summed Pain Intensity (SPI)/ Area under the Curve (AUC). A: Blue line represents pain intensity reported by the placebo arm. B: Red line represents pain intensity reported by the active arm. C: Gray area represents treatment effect (mean placebo NPRS - mean active NPRS).

Table 4 presents a summary of available endpoints for pre/intra-operative dosing and postoperative dosing paradigms.

Table 4 Pre-/ Intra-Operative Dosing Vs Postoperative Dosing

Typical Secondary Endpoints Measures of Analgesic Onset

A Kaplan-Meier methodology is utilized to analyze the following endpoints that are derived from 2-stopwatch data:29

Time to Perceptible Pain Relief: an endpoint derived from the median time at which study subjects stop the first stopwatch (which is labeled “Perceptible Relief”). Time to Meaningful Pain Relief: an endpoint derived from the median time at which study subjects stop the second stopwatch (which is labeled “Meaningful Relief”). Subjects are considered to have achieved meaningful pain relief only if they hit the meaningful pain relief stopwatch before (1) receiving any dose of rescue analgesic or (2) receiving their 2nd scheduled dose of study drug. Time to Onset, also known as Time to Confirmed Perceptible Pain Relief: a derived endpoint that considers the time to perceptible pain relief only among subjects who also eventually achieve meaningful pain relief.

An additional method of analyzing analgesic onset is to determine the first time point at which the NPRS scores begin to diverge by a prespecified amount between treatment arms (generally referred to as time-specific pain intensity differences).

Measurement of Rescue Analgesics

Rescue analgesics are provided to study subjects only when needed/requested. As such, the amount of rescue analgesics consumed by the study subject can serve as a surrogate measure for how much pain that subject is experiencing.30 It is therefore common to tabulate and compare the total number of doses of rescue drug received in each study arm and report rescue-related efficacy endpoints.31,32 If the rescue analgesic regimen involves multiple opioids, an opioid equivalence chart can be used to facilitate the analysis.33

The time elapsed between the administration of the first dose of study drug and the request/receipt of the first dose of rescue drug is commonly calculated and compared between treatment groups. This measure can provide information about analgesic offset.

Summary Table of Bunionectomy Acute Pain Clinical Trials Since 2008 Methods Data Sources Searched and Criteria for Inclusion/ Exclusion of Publications and Studies Summary Table of Bunionectomy Studies (Table 5)

MEDLINE/ PubMed was searched for all relevant studies published between January 1, 2008 and December 5th, 2023. Relevant studies included any randomized, double-blind, controlled clinical trial in adults ≥18 years old, that tested a pharmacologic analgesic agent in a bunionectomy acute pain trial. The search was performed for “bunionectomy” and the advanced search option limited results to “clinical trial”, “clinical trial, Phase II”, “clinical trial, Phase III”, “clinical trial, Phase IV”, in Humans, and in Adults. Search: (“bunionectomies”[All Fields] OR “bunionectomy”[All Fields]) AND ((clinicaltrial[Filter] OR clinicaltrialphaseii[Filter] OR clinicaltrialphaseiii[Filter] OR clinicaltrialphaseiv[Filter]) AND (humans[Filter]) AND (2008/1/1:2023/10/1[pdat]) AND (alladult[Filter])). A total of 38 publications were identified in the search. The authors reviewed each abstract and publication to determine if the publication met the criteria for our narrative review.

Table 5 Bunionectomy Studies

Additionally, clinicaltrials.gov was searched for unpublished bunionectomy studies using the following criteria: (1) Condition/disease: bunionectomy and then further limited to (2) completed studies, (3) Phase II or III, (4) interventional studies, (5) industry sponsored, and (6) had a primary completion date between January 1st, 2008 and December 5th, 2023.

FDA Summary Basis of Approval documents were reviewed for any additional information missing from publications and/or clincialtrials.gov.

All studies that were identified either through a publication or a clinicaltrials.gov search were included in the table, regardless of availability of data. Dashes in the table represent missing data that the authors were unable to find in public sources.

Rescue Table (Table 6)

All studies from the main search for which sufficient information related to rescue medication was available are included in Table 6. These studies had Studies publicly-available details on A) protocol-allowed rescue medication and B) the rate of early terminations due to lack of efficacy in the placebo arm.

Table 6 Placebo Arm Rescue Use and Efficacy Terminations in Bunionectomy Studies

Demographics Table (Table 7)

The 5 most recent publications were reviewed and common demographic data was compiled in a table Weighted averages were obtained within an individual study and then a weighted average was calculated across all studies. A limited number of recent studies were reviewed for Table 7 as the table is simply meant to provide a brief qualitative overview of demographic data. Additionally, data from recent available manuscripts may better reflect current demographic patterns in bunionectomy trials than data from older studies.

Table 7 Demographic Characteristics of Bunionectomy Subjects

Analysis Rescue Medication

Rescue analgesics are ethically required in acute pain studies, but they confound experimental data. In bunionectomy studies rescue is frequent in both the placebo arm (≈95% of placebo subjects receive at least one dose of rescue) and the active arm (≈85% of active subjects receive at least one dose of rescue).51 As such, the choice of rescue is an important study design element. An ideal rescue regimen is a balance between:

Strict rescue, which can give rise to unacceptably high terminations due to lack of efficacy (resulting in a high degree of missing data), and Liberal rescue, which can excessively confound study data (Figure 6).

Figure 6 Balancing rescue regimens *Ethical considerations around rescue medication are important, and are discussed in other sources.51

The optimal way to interrogate a rescue regimen is to examine the placebo arm of past bunionectomy studies and calculate the rate of early terminations due to lack of efficacy. If a rate is too high (greater than ≈20%) then the experiment used too strict a rescue regimen (ie, not enough rescue). On the other hand, if there were very few efficacy terminations in the placebo arm (less than ≈2%), then the experiment likely used too liberal a rescue regimen (ie, too much rescue).

Table 6 shows rescue regimens and placebo dropout rates due to lack of efficacy in bunionectomy studies.

Enrollment Rates

To estimate the average enrollment rate (subjects enrolled per site per month) for bunionectomy acute pain trials, we examined enrollment data from clinicaltrials.gov (CTG). Adequate data was available for 47 of the 53 studies in Table 5. The remaining 6 studies did not have all necessary data to calculate an enrollment rate listed on CTG.34,35,38,39,41,42 Enrollment rate was calculated with the following formula:

Total study n ÷ number of study centers ÷ enrollment period in months

The enrollment period was considered to be the time from the “Study Start Date” to the “Primary Completion Date”.

For these 47 studies, the unweighted mean enrollment rate was 15.2 subjects per site per month.

Reported enrollment periods derived from CTG data are sometimes longer than the actual active enrollment time of the study. This is because a CTG enrollment period may include pauses during which a study was not actively enrolling. As such the actual mean enrollment rate for these studies may be somewhat higher than 15.2, if only active enrollment time is considered.

Demographics

Table 7 shows a weighted average of demographic information from the 5 most recent bunionectomy publications* as of December 2023:

Dental Impaction Pain Model (DIPM) versus Bunionectomy

DIPM, in which pain is assessed after third molar extraction surgery, is a common and useful hard tissue pain model. Dental studies can be recruited more rapidly (using fewer centers) and more cost-effectively than can bunionectomy studies.16 The experimental clarity of dental studies is high (higher standardized effect sizes than bunionectomy).16 As such, dental is an excellent model for:

Initial proof of concept Dose ranging, and Exploring PK/PD relationships.

The dental model is generally regarded as a single-dose model that provides assay sensitivity for 6–12 hours after surgery.52 It has not been accepted by US or European regulators as a pivotal acute pain model in recent years,18 because it is considered to have low clinical relevance, and does not provide adequate information on efficacy past 6–12 hours (and therefore cannot be used to assess multi-dose efficacy).

Discussion

The three most common hard tissue acute pain models are dental impaction (DIPM), bunionectomy and total knee arthroplasty (TKA). DIPM is a rapidly-recruiting, extremely sensitive model that is considered to have low clinical significance. TKA on the other hand is highly clinically relevant but experimentally confounded. Bunionectomy represents a compromise between these two extremes. It is a model with acceptable assay sensitivity and reasonable clinical relevance (see Figure 7).

Figure 7 Comparison of common hard tissue acute pain models.

Bunionectomy maintains its assay sensitivity for approximately 72–96 hours after surgery.31,53 As such the model is able to provide information on the multi-dose behavior of an experimental agent. For this reason, regulators in the United States and the European Union have accepted bunionectomy as a pivotal model for putative analgesic candidates.

The triad of good assay sensitivity, reasonable clinical relevance and regulatory acceptance explains the popularity of bunionectomy as an acute pain surgical model.

Data Sharing Statement

Data sharing is not applicable to this article, as no new data were created or analyzed for the article.

Disclosure

Neil Singla, MD is the founder of Lotus Clinical Research, a full-service contract research organization, research site network and consulting firm that specializes in analgesic clinical trials. Lotus generates revenue from the performance of studies in acute pain and other therapeutic areas. The authors report no other conflicts of interest in this work.

Timothy Rogier is an independent researcher and consultant specializing in acute and chronic pain clinical trials.

Diana S. Meske, PhD is the Chief Operating Officer of Chariton Pharmaceuticals and Owner and Principle Consultant of Alivio Clinical Consulting, which consults to industry clients on analgesic clinical trials and drug development.  Chariton Pharmaceuticals is developing a treatment for rheumatoid arthritis pain.

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