Consensus Guidelines on Interventional Therapies for Knee Pain (STEP Guidelines) from the American Society of Pain and Neuroscience

Figures & data

Table 1 USPSTF Hierarchy of Studies by the Type of Design

Evidence Level	Study Type
I	At least one controlled and randomized clinical trial, properly designed
II-1	Well-designed, controlled, nonrandomized clinical trials
II-2	Cohort or case studies and well-designed controls, preferably multicenter
II-3	Multiple series compared over time, with or without intervention, and surprising results in noncontrolled experiences
III	Clinical experience-based opinions, descriptive studies, clinical observations, or reports of expert committees

Table 2 USPSTF Meaning of Recommendation Degrees

Degree of Recommendation	Meaning
A	Extremely recommendable (good evidence that the measure is effective and that benefits outweigh the harms)
B	Recommendable (at least moderate evidence that the measure is effective and that benefits exceed harms)
C	Neither recommendable nor inadvisable (at least moderate evidence that the measure is effective, but benefits are similar to harms and a general recommendation cannot be justified)
D	Inadvisable (at least moderate evidence that the measure is ineffective or that the harms exceed the benefits)
I	Insufficient, low-quality, or contradictory evidence; the balance between benefit and harms cannot be determined

Table 3 USPSTF Strength of Consensus

Strength of Consensus	Definition
Strong	>80% consensus
Moderate	50–79% consensus
Weak	<49% consensus

Table 4 Level I–V Definitions

Level	Descriptor	Definition
Level I	Strong	Evidence obtained from 2 or more relevant high-quality randomized controlled trials for effectiveness. or Evidence obtained from 4 or more relevant high-quality observational studies or large case series for assessment of preventive measures, adverse consequences, effectiveness of other measures.
Level II	Moderate	Evidence obtained from at least one relevant high-quality randomized controlled trial or multiple relevant moderate or low quality randomized controlled trials. or Evidence obtained from at least 2 high-quality relevant observational studies or large case series for assessment of preventive measures, adverse consequences, and effectiveness of other measures.
Level III	Fair	Evidence obtained from at least one relevant high-quality nonrandomized trial or observational study with multiple moderate or low-quality observational studies. or At least one high-quality relevant observational study or large case series for assessment of preventive measures, adverse consequences, effectiveness of other measures.
Level IV	Limited	Evidence obtained from multiple moderate or low-quality relevant observational studies. or Evidence obtained from moderate-quality observational studies or large case series for assessment of preventive measures, adverse consequences, and effectiveness of other measures.
Level V	Consensus based	Opinion or consensus of a large group of clinicians and/or scientists for effectiveness as well as to assess preventive measures, adverse consequences, effectiveness of other measures.

Table 5 NEATS Recommendations

Rating for Strength of Recommendation
Strong	There is high confidence that the recommendation reflects best practice. This is based on: a) strong evidence for a true net effect (eg, benefits exceed harms); b) consistent results, with no or minor exceptions; c) minor or no concerns about study quality; and/or d) the extent the panelists’ agreement. Other compelling considerations (discussed in the guideline’s literature review and analyses) may also warrant a strong recommendation.
Moderate	There is moderate confidence that the recommendation reflects best practice. This is based on: a) good evidence for a true net effect (eg, benefits exceed harms); b) consistent results, with minor and/or few exceptions; c) minor and/or few concerns about study quality; and/or d) the extent of panelists’ agreement. Other compelling considerations (discussed in the guideline’s literature review and analyses) may also warrant a moderate recommendation.
Weak	There is some confidence that the recommendation offers the best current guidance for practice. This is based on: a) limited evidence for a true net effect (eg, benefits exceed harms); b) consistent results, but with important exceptions; c) concerns about study quality; and/or d) the extent of panelists’ agreement. Other considerations (discussed in the guideline’s literature review and analyses) may also warrant a weak recommendation.

Table 6 “Special” Maneuvers for Examining the Knee

Test	Positive Test Indication
McMurray’s test	Medial or lateral meniscus injury/tear
Lachman’s test	Anterior cruciate ligament (ACL) injury/tear
Pivot shift test	ACL deficiency/acute vs chronic injury
Reverse pivot shift test	Torn posterior collateral ligament (PCL), lateral collateral ligament (LCL), arcuate complex and popliteal fibular ligament (PFL)
Anterior drawer test	ACL injury/tear
Posterior drawer test	PCL injury/tear (most accurate test to diagnose this issue)
Dial test	Combined posterolateral corner injury and PCL injury
Valgus stress test	Medial collateral ligament (MCL) injury/tear
Varus stress test	LCL injury/year
Patellar grind test	Patellofemoral chondromalacia
Apley’s distraction test	Ligamentous injury/tear
Apley’s compression test	Meniscus injury/tear
Noble test	IT band syndrome
Ober test	IT band syndrome

Table 7 Budapest Criteria for CRPS Diagnosis

1. Continuing pain that is disproportionate to the inciting event
2. At least one sign in 3 of 4 categories by history	Sensory:	Hyperesthesia, allodynia
	Vasomotor:	Temperature abnormalities/asymmetry, skin color changes/asymmetry
	Sudomotor:	Edema, sweating changes/asymmetry
	Motor/trophic:	Decreased range of motion, weakness, dystonia, hair, nail, or skin changes
3. At least one sign in 2 of 4 categories by exam	Sensory:	Evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch, temperature sensation, deep somatic pressure, and/or joint movement)
	Vasomotor:	Evidence of temperature asymmetry > 1°C, skin color changes/asymmetry
	Sudomotor:	Evidence of edema, sweating changes, asymmetry
	Motor/trophic:	Evidence of decreased range of motion, weakness, tremor, dystonia, hair, nail, skin changes
4. There is no other diagnosis that better explains the symptoms

Table 8 Intrinsic or Extrinsic Etiologies of Post-TKA Pain

Intrinsic Causes	Extrinsic Causes	Rare Causes
Infection	Hip pathology	Synovitis
Implant mal-positioning, loosening, failure	Spine pathology	Recurrent hemarthrosis
Knee instability	Vascular pathology	Nerve related (cutaneous neuroma, CRPS, fibromyalgia, Tourniquet palsy)
Extensor mechanism disorders (quadriceps/patellar tendon rupture)	Tendinitis, bursitis	Worker’s compensation
Arthrofibrosis	Metal sensitivity	Heterotopic ossification
	Minimal preoperative knee OA	Psychiatric disorder

Table 9 Evidence Table Regarding NSAIDs

Study	Details	Results	USPSTF Rating
Adatia et al, 2012^Citation345	Systematic review on ibuprofen for knee and hip OA: 10 RCTs, n=1777	Ibuprofen effective and relatively safe at low doses for mild-to-moderate OA of knee	Level I
Smith et al, 2016^Citation346	Systematic review on celecoxib/non-selective NSAIDs, less potent opioids, and more potent opioids for knee OA: 9 RCTs on celecoxib, n=2937; 4 RCTs on non-selective NSAIDs, n=587	No statistical significance in WOMAC reduction between Celebrex/non-selective NSAIDs and opioids	Level I
Da Costa et al, 2021^Citation58	Systematic review on NSAIDs and opioids for knee OA: 192 RCTs, n=102,829	NSAIDs are clinically effective for improving pain and function with knee OA; safe when used for intermittent short- to midterm periods of time; Etoricoxib 60 mg/day and diclofenac 150 mg/day most effective	Level I

Table 10 Evidence Table Regarding Topicals

Study	Study Type	Details	Systematic Literature Review Grading	USPSTF Rating
Barthel et al, 2009^Citation108	RCT	N=492; Diclofenac gel versus vehicle with follow-up at 3 months, Outcome measures: VAS and WOMAC	Level 1 study based on all criteria	Level I
Rother et al, 2007^Citation110	RCT	N=324; Epicutaneous ketoprofen in Transfersome (IDEA-033) versus oral celecoxib and placebo with follow-up at 6 weeks, Outcome measures: WOMAC and patient global assessment (PGA)	Level 2 based on strong quality scoring for Cochrane and moderate scoring for QAREL and IPM	Level I
Conaghan et al, 2013^Citation109	RCT	N=1395; Topical ketoprofen in Transfersome gel (IDEA-033) versus ketoprofen-free vehicle (TDT 064) and oral celecoxib with follow-up at 12 weeks, Outcome measures: WOMAC	Level 2 based on strong quality scoring for Cochrane and moderate scoring for QAREL and IPM	Level I
Bruhlmann and Michel 2003^Citation111	RCT	N=103; Diclofenac hydroxyethylpyrrolidine (DHEP) patch versus placebo with follow-up at 2 weeks, Outcome measures: spontaneous pain and Lequesne’s Index	Level 2 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Underwood et al, 2008^Citation103	RCT and observational	N=282 (RCT) and 303 (observational) with follow-up at 1 year, Outcome measures: WOMAC and SF-36	Level 1 study based on all criteria	Level II-1
Rother and Conaghan, 2013^Citation119	RCT	N=555; Topical ketoprofen gel versus ketoprofen-free gel with follow-up at 12 weeks, Outcome measures: WOMAC	Level 2 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Yataba et al, 2016^Citation112	RCT	N=633; S-flurbiprofen plaster versus flurbiprofen patch with follow-up at follow-up at 2 weeks, Outcome measures: VAS	Level 2 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Tiso et al, 2010^Citation118	RCT	N=20; Oral versus topical ibuprofen with follow-up at 2 weeks, Outcome measures: WOMAC and SF-12	Level 3 study based on all criteria	Level II-1
Baraf et al, 2011^Citation104	RCT	N=976; Topical diclofenac sodium 1% gel versus vehicle with follow-up at 12 weeks, Outcome measures: WOMAC, VAS, and pain on movement	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Baraf et al, 2010^Citation117	RCT	N=420; Topical diclofenac sodium 1% gel versus vehicle with follow-up at 6 months, Outcome measures: WOMAC, spontaneous pain, and global rating of benefit	Level 1 study based on all criteria	Level I
Roth et al, 2004^Citation105	RCT	N=326; Topical pensaid versus vehicle with follow-up at 12 weeks, Outcome measures: WOMAC, physical function subscales and a patient global assessment	Level 1 study based on all criteria	Level I
Bookman et al, 2004^Citation107	RCT	N=248; Topical diclofenac gel versus vehicle with follow-up at 4 weeks, Outcome measures: WOMAC and PGA	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Baer et al, 2005^Citation113	RCT	N=216; Topical diclofenac versus vehicle with follow-up at 6 weeks, Outcome measures: WOMAC and PGA	Level 2 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Kneer et al, 2013^Citation114	RCT	N=866; Ketoprofen in Transfersome® gel (IDEA-033) compared with the ketoprofen-free vehicle (TDT 064) with follow-up at 12 weeks, Outcome measures: WOMAC, PGA and Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) responder rates	Level 2 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Niethard et al, 2005^Citation106	RCT	N=238; topical diclofenac diethylamine gel 1.16% versus placebo with follow-up at 3 weeks, Outcome measures: WOMAC and PGA	Level 1 study based on all criteria	Level I
Varadi et al, 2013^Citation115	RCT	N=64; Transdermal ibuprofen formulation (VALE®-ibuprofen) containing 10% ibuprofen versus placebo with follow-up at 2 weeks, Outcome measures: WOMAC and VAS	Level 2 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Wadsworth et al, 2016^Citation116	RCT	N=260; Diclofenac sodium 2% topical solution versus vehicle with follow-up at 4 weeks, Outcome measures: WOMAC and PGA	Level 2 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I

Table 11 Evidence Table Regarding Intra-Articular Corticosteroid Injections

Study	Study Type	Details	Systematic Literature Review Grading	USPSTF Rating
Arroll et al 2004^Citation347	Meta Analysis	10 studies; IACS vs placebo with follow-up at 24 weeks, Outcome measures: VAS	Level 2 study based on strong criteria for QAREL and Cochrane and moderate quality for IPM	Level I
McAlindon et al, 2017^Citation186	RCT	N=140; IACS q4 months vs placebo with 2-year follow-up, Outcome measures: WOMAC, cartilage volume	Level 1 study based on all criteria	Level I
Jüni et al, 2015^Citation161	Systematic review	27 included studies, N=1767; IACS vs placebo with follow-up to 26 weeks; Outcome measures: WOMAC, joint space narrowing, quality of life and function	Level 1 study based on all criteria	Level I
van Middelkoop et al, 2016^Citation348	Meta analysis	7 studies, N=620; IACS vs placebo with follow-up 4 weeks to 1 year, Outcome measures: VAS, WOMAC	Level 1 study based on all criteria	Level I
Concoff et al, 2017^Citation349	Systematic review	30 studies, N=5848; single vs multiple intra-articular hyaluronic acid (IAHA) injections with follow-up at 13–26 weeks, Outcome measures: WOMAC, VAS, Knee Osteoarthritis Outcome Score (KOOS), Musculoskeletal Outcomes Data Evaluation and Management System (MODEMS), Index of Severity for Osteoarthritis for the Knee (ISK)	Level 1 study based on all criteria	Level I
Richette et al, 2015^Citation350	Meta analysis	8 studies, N=2199; IAHA vs placebo with follow-up at 3 months, Outcome measures: pain intensity, WOMAC	Level 1 study based on all criteria	Level I
van der Weegen et al, 2015^Citation351	RCT	N=196; IAHA vs placebo with follow-up at 1, 3, and 6 months, Outcome measures: ROM, VAS, and WOMAC	Level 2 study based on strong criteria for QAREL and Cochrane and moderate quality for IPM	Level I
Bannuru et al, 2009^Citation352	Meta analysis	7 studies, N=606; IACS vs IAHA with follow-up at 2, 4, 8, 12, and 26 weeks, Outcome measures: pain change from baseline	Level 1 study based on all criteria	Level I
Yilmaz et al, 2019^Citation353	RCT	N=90; IACS vs IA-NSAIDs with follow-up at 1, 3, and 6 months, Outcome measures: VAS and WOMAC	Level 2 study based on all criteria	Level I
Riis et al, 2017^Citation354	RCT	N=100; IACS vs placebo with follow-up at 14 and 26 weeks, Outcome measures: KOOS-Pain	Level 2 study based on strong criteria for QAREL and Cochrane and moderate quality for IPM	Level I
Bodick et al, 2014^Citation355	RCT	N=228; a immediate release vs extended release IACS with follow-up at 8, 10, and 12 weeks, Outcome measures: numeric rating scale (NRS), WOMAC	Level 2 study based on strong criteria for QAREL and Cochrane and moderate quality for IPM	Level I

Table 12 Evidence Table Regarding Hyaluronic Acid

Study	Study Type	Details	Systematic Literature Review Grading	USPTF Rating
Petrella et al, 2002^Citation356	RCT	N=120; IAHA vs NSAIDs vs placebo with follow-up at 4 and 12 weeks, Outcome measures: VAS, WOMAC, function	Level 2 study based on strong criteria for QAREL and Cochrane and moderate quality for IPM	Level I
Miller et al, 2020^Citation166	Meta analysis	N=831; IAHA vs NSAIDs with 4–26 weeks follow-up, Outcome measures: pain and function	Level 1 study based on all criteria	Level I
Bellamy et al, 2006^Citation357	Systematic review	76 included studies; IAHA vs placebo, CS, NSAIDs, PT, exercise, arthroscopy, CAM, with follow-up to 18 months; Outcome measures: pain and function	Level 1 study based on all criteria	Level I
Stitik et al, 2017^Citation358	Meta analysis	24 studies, N=2168; IAHA vs placebo, PRP, 3 vs 5 HA injections, NSAIDs, arthroscopy, CS, with follow-up 12–52 weeks, Outcome measures: VAS, WOMAC	Level 1 study based on all criteria	Level I
Concoff et al, 2017^Citation349	Systematic review	3 studies, N=5848; single vs multiple IAHA injections with follow-up at 13–26 weeks, Outcome measures: WOMAC, VAS, KOOS, MODEMS, ISK	Level 1 study based on all criteria	Level I
Campbell et al, 2015^Citation359	Systematic review	14 studies, N=20,049; PRFA: IAHA vs placebo, NSAIDs, or CS with follow-up to 6 months, Outcome measures: VAS, pain, function, range of motion, activity-related knee pain, pooled effect size, Lequesne score, WOMAC	Level 1 study based on all criteria	Level I
Richette et al, 2015^Citation350	Meta analysis	8 studies, N=2199; IAHA vs placebo with follow-up at 3 months, Outcome measures: pain intensity, WOMAC	Level 1 study based on all criteria	Level I
van der Weegen et al, 2015^Citation351	RCT	N=196; IAHA vs placebo with follow-up at 1, 3, and 6 months, Outcome measures: range of motion (ROM), VAS, and WOMAC	Level 2 study based on strong criteria for QAREL and Cochrane and moderate quality for IPM	Level I
Navarro-Sarabia et al, 2011^Citation360	RCT	N=306; 4 cycles of 5 IAHA vs placebo with follow-up at 6, 12, 24 and 36 months, Outcome measures: VAS and OARSI criteria	Level 1 study based on all criteria	Level I
Strand et al, 2012^Citation361	RCT	N=379; a single IAHA vs placebo with follow-up at 13 weeks, Outcome measures: VAS and WOMAC	Level 2 study based on strong criteria for QAREL and Cochrane and moderate quality for IPM	Level I
Berenbaum et al, 2012^Citation362	RCT	N=426; IAHA vs IAHA with follow-up at 6, 14, 20 and 26 weeks, Outcome measures: VAS, WOMAC, intermittent and constant osteoarthritis pain index (ICOAP), Lequesne, OMERACT	Level 2 study based on strong criteria for QAREL and Cochrane and moderate quality for IPM	Level I
Arden et al, 2013^Citation363	RCT	N=218; a single IAHA vs placebo with follow-up at 2, 4, and 6 weeks, Outcome measures: WOMAC	Level 3 study based on intermediate criteria for QAREL and Cochrane and fair quality for IPM	Level I

Figure 1 Illustration of the innervation of the knee.

Table 13 Evidence Table Regarding Genicular Nerve Ablations

Study	Study Type	Details	Systematic Literature Review Grading	USPSTF Rating
Alcidi et al, 2007^Citation176	RCT	N=40; TRFA vs TENS with follow-up at 30 days, Outcome measures: VAS and Lequesne’s index	Level 3 study based on all criteria	Level II-1
Choi et al, 2011^Citation177	RCT	N=38; TRFA vs sham with follow-up at 4 and 12 weeks, Outcome measures: VAS and Oxford Knee Score (OKS)	Level 2 based upon moderate quality scoring for Cochrane and QAREL and intermediate study scoring for IPM	Level I
Ikeuchi et al, 2011^Citation181	n-RCT	N=35; RFA vs nerve block with follow-up at 1, 3 and 6 months; Outcome measures: VAS and WOMAC	Level 3 study based on all criteria	Level II-2
Shen et al, 2016^Citation364	RCT	N=54; TRFA w/ PRP+HA vs PRP+HA with follow-up 3 months, Outcome measures: VAS, American Knee Society Score (AKSS), Short-Form Health Survey 36-item (SF-36)	Level 2 based upon moderate quality scoring for Cochrane and intermediate study scoring for IPM and QAREL	Level II-1
Takahashi et al, 2016^Citation365	RCT	N=17; RFA vs microwave diathermy with follow-up at 1 and 3 weeks, Outcome measures: Japan Orthopaedic Association (JOA) scale, Lequesne Index	Level 3 based upon moderate quality scoring for QAREL and IPM and low study scoring for Cochrane	Level II-1
Gulec et al, 2017^Citation182	Case Series	N=100; Percutaneous RFA: monopolar vs bipolar with follow-up at 12 weeks, Outcome measures: VAS	Level 3 study based on all criteria	Level II-2
Qudsi-Sinclair et al, 2018^Citation179	RCT	N=28 post-TKA; TRFA vs sham with follow-up at 12 months, Outcome measures: VAS, OKS and KSS	Level 2 based upon moderate quality scoring for QAREL and IPM and intermediate study scoring for Cochrane	Level I
Sari et al, 2018^Citation170	RCT	N=73; TRFA vs IAS + morphine with follow-up at 1 and 3 months, Outcome measures: VAS and WOMAC	Level 3 study based on all criteria	Level II-1
Davis et al, 2018^Citation174	RCT	N=151; CRFA vs IAS with follow-up at 6 and 12 months, Outcome measures: NRS and OKS	Level 2 based upon intermediate quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
El-Hakeim et al, 2018^Citation178	RCT	N=60; Conventional RFA vs oral analgesics with follow-up at 2 weeks, 3 and 6 months, Outcome measures: VAS and WOMAC	Level 3 based upon moderate quality scoring for QAREL and IPM and low study scoring for Cochrane	Level I
McCormick et al, 2018^Citation366	RCT	N=53; Conventional RFA with follow-up at 1, 3 and 6 months, Outcome measures: NRS and WOMAC	Level 3 based upon moderate quality scoring for QAREL and IPM and low study scoring for Cochrane	Level II-2

Table 14 Evidence Table Regarding Platelet-Rich Plasma

Study	Study Type	Details	Systematic Literature Review Grading	USPSTF Rating
Cerza et al, 2012^Citation367	RCT	N=120; PRP vs HA with follow-up at 24 weeks, Outcome measures: WOMAC	Level 3 study based on all criteria	Level I
Filardo et al, 2012^Citation368	RCT	N=109; PRP vs HA with follow-up at 12 months, Outcome measures: IKDC, EQ-VAS, Tegner, KOOS and ROM	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Spaková et al, 2012^Citation369	Observational, Prospective	N=120; PRP vs HA with follow-up at 6 months, Outcome measures: WOMAC and NRS	Level 3 based upon intermediate quality scoring for QAREL and Cochrane and low study scoring for IPM	Level II-2
Patel et al, 2013^Citation370	RCT	N=78; PRP vs PRP x2 vs saline with follow-up at 6 months, Outcome measures: WOMAC and VAS	Level 2 based upon moderate quality scoring for QAREL and Cochrane and intermediate study scoring for IPM	Level I
Cole et al, 2015^Citation371	RCT	N=111; PRP vs HA with follow-up at 1 year, Outcome measures: WOMAC, IKDC, VAS, and Lysholm	Level 1 study based on all criteria	Level I
Filardo et al 2015^Citation372	RCT	N=443; PRP vs HA with follow-up at q2 months, Outcome measures: IKDC, Tegner, VAS, and EuroQol	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Raeissadat et al, 2015^Citation373	RCT	N=160; PRP vs HA with follow-up at 12 months, Outcome measures: WOMAC and SF-36	Level 3 study based on all criteria	Level I
Forogh et al, 2016^Citation374	RCT	N=41; PRP vs corticosteroid with follow-up at 6 months, Outcome measures: KOOS, 20MW, ROM, and VAS	Level 1 study based on all criteria	Level I
Lana et al, 2016^Citation375	RCT	N=105; PRP vs HA vs PRP and HA with follow-up at 12 months, Outcome measures: WOMAC and VAS	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Montañez-Heredia et al, 2016^Citation376	RCT	N=53; PRP vs HA with follow-up at 6 months, Outcome measures: VAS, KOOL and EuroQol	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Paterson et al, 2016^Citation377	RCT	N=37; photo-activated PRP vs HA with follow-up at 12 weeks, Outcome measures: VAS, KOOS, and KQoL	Level 2 based on moderate quality scoring for Cochrane and QAREL and intermediate study scoring for IPM	Level I
Simental-Mendía et al, 2016^Citation378	RCT	N=65; PRP vs oral acetaminophen with follow-up at 24 weeks, Outcome measures: VAS, WOMAC and SF-12	Level 3 study based on all criteria	Level-I
Smith et al, 2016^Citation379	RCT	N=30; PRP vs saline with follow-up 1 year, Outcome measures: WOMAC	Level 1 study based on all criteria	Level I
Duymus et al, 2017^Citation380	RCT	N=102; PRP vs HA vs Ozone with follow-up at 12 months, Outcome measures: WOMAC and VAS	Level 2 based on moderate quality scoring for Cochrane and intermediate scoring for QAREL and IPM	Level I
Görmeli et al, 2017^Citation381	RCT	N=162; PRP vs HA with follow-up at 6 months, Outcome measures: VAS and IKDC	Level 1 study based on all criteria	Level I
Güvendi et al, 2017^Citation194	Observational, Prospective	N=50; PRP x1 vs PRP x3 vs corticosteroid x1 with follow-up at 6 months, Outcome measures: WOMAC, VNS, Lequesne, and HADS	Level 3 study based on all criteria	Level II-2
Jubert et al, 2017^Citation193	RCT	N=75, PRP vs corticosteroid with follow-up at 6 months, Outcome measures: KOOS and SF-36	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Lisi et al 2017^Citation382	RCT	N=30; PRP vs HA with follow-up at 6 months, Outcome measures: WOMAC, Lysholm, Tegner, AKSS, Lequesne and VAS	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Ahmad et al, 2018^Citation383	RCT	N=89; PRP vs HA with follow-up at 6 months, Outcome measures: VAS and synovium appearance	Level 2 based on moderate quality scoring for Cochrane and intermediate scoring for QAREL and IPM	Level I
Angoorani et al, 2018^Citation384	RCT	N=54; PRP vs PT/TENS with follow-up at 8 weeks, Outcome measures: VAS	Level 2 based on moderate quality scoring for Cochrane and QAREL fair study scoring for IPM	Level I
Buendía-López et al, 2018^Citation385	RCT	N=106; NSAIDs vs HA vs PRP with follow-up at 12 months; Outcome measures: WOMAC and VAS	Level 2 study based on all criteria	Level I
Di Martino et al, 2018^Citation386	RCT	N=167; PRP vs HA with follow-up at 24 months, Outcome measures: IKDC, EuroQol, Tegner	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Gaballa et al, 2018^Citation387	RCT	N=200; PRP vs HA vs Plasma w/ growth factors vs Ozone with follow-up at 12 months, Outcome measures: VAS, WOMAC, and Lequesne	Level 3 study based on all criteria	Level I
Khan et al, 2018^Citation388	RCT	N=150; PRP vs corticosteroid with follow-up at 6 months, Outcome measures: WOMAC and VAS	Level 3 based upon intermediate quality scoring for QAREL and Cochrane and low study scoring for IPM
Lin et al, 2018^Citation389	RCT	N=87; PRP vs HA vs saline with follow-up at 12 months, Outcome measures: WOMAC and IKDC	Level 1 study based on all criteria	Level I
Louis et al, 2018^Citation390	RCT	N=54; PRP vs HA with follow-up at 6 months, Outcome measures: WOMAC and VAS	Level 1 based on strong quality scoring for Cochrane and QAREL and moderate study scoring for IPM	Level I
Nabi et al, 2018^Citation391	RCT	N=67; PRP vs Triamcinolone with follow-up at 6 months, Outcome measures: KOOS and VAS	Level 2 study based on all criteria	Level I
Rahimzadeh et al, 2018^Citation392	RCT	N=44; PRP vs Prolotherapy with follow-up at 6 months, Outcome measures: WOMAC	Level 1 study based on all criteria	Level I
Su et al, 2018^Citation198	RCT	N=86; IO PRP vs IA PRP vs HA with follow-up at 18 months, Outcome measures: WOMAC and VAS.	Level 3 study based on all criteria	Level I
Wu et al, 2018^Citation393	RCT	N=20; PRP vs Saline with follow-up at 6 months, Outcome measures: WOMAC	Level 2 based on moderate quality scoring for Cochrane and QAREL and intermediate study scoring for IPM	Level I
Huang et al, 2019^Citation394	RCT	N=120; PRP vs HA vs corticosteroid with follow-up at 12 months, Outcome measures: WOMAC and VAS	Level 3 study based on all criteria	Level I
Anz et al, 2020^Citation395	RCT	N=90; PRP vs bone marrow aspirate concentrate (BMAC) with follow-up at 12 months, Outcome measures: WOMAC and IKDC	Level 2 based on moderate quality scoring for Cochrane and intermediate scoring for QAREL and IPM	Level I
Elksniņš-Finogejevs et al, 2020^Citation396	RCT	N=40; PRP vs Triamcinolone with follow-up at 1 year, Outcome measures: VAS, IKDC, and KSS	Level 2 based on moderate quality scoring for Cochrane and QAREL and intermediate study scoring for IPM	Level I
Kesiktas et al, 2020^Citation397	RCT	N=54; PRP vs HA vs Prostrolane with follow-up at 3 months, Outcome measures: WOMAC, VAS and HAC	Level 2 based on moderate quality scoring for Cochrane and QAREL and intermediate study scoring for IPM	Level I
Pishgahi et al, 2020^Citation398	RCT	N=92; PRP vs Prolotherapy vs autologous conditioned serum with follow-up at 6 months, Outcome measures: WOMAC and VAS	Level 3 study based on all criteria	Level I
Raeissadat et al, 2020^Citation399	RCT	N=102; PRP-derived growth factor vs HA with follow-up at 12 months, Outcome measures: WOMAC and Lequesne	Level 2 based on moderate quality scoring for Cochrane and QAREL and intermediate study scoring for IPM	Level I
Reyes-Sosa et al, 2020^Citation400	RCT	N=60; PRP vs oral Celecoxib with follow-up 12 months, Outcome measures: WOMAC	Level 3 based upon intermediate quality scoring for QAREL and Cochrane and low study scoring for IPM	Level I

Table 15 Evidence Table Regarding Amniotic Tissue

Study	Study Type	Details	Systematic Literature Review Grading	USPSTF Rating
Vines et al 2015^Citation215	Open-label prospective feasibility study	N=6; Study demonstrates feasibility of one intra-articular injection with amniotic suspension allografts for treating knee osteoarthritis.	Level 4 based on limited quality scoring for Cochrane and QAREL	Level II-3
Castellanos et al 2019^Citation216	Prospective, investigator-initiated, single-center pilot study	N=20; Intra-articular injection of amniotic membrane/umbilical cord particulate demonstrates preliminary safety, relief of pain, and improvement in function in patients with knee OA with severities varying from BML Grades 0–3. A second injection may be needed in obese individuals.	Level 4 based on limited quality scoring for Cochrane and QAREL	Level II-3
Mead et al 2020^Citation217	Single center, investigator-initiated, retrospective study	N=42; An intra-articular knee injection of amniotic membrane/umbilical cord particulate may be helpful in relieving pain and improving function in those with Kellgren–Lawrence (KL) grade 3 or 4. This treatment may delay knee replacement for up to one year.	Level 4 based on limited quality scoring for Cochrane and QAREL	Level II-3
Farr et al 2019^Citation218	RCT	N=200; ASA versus HA versus saline with follow-up at 6 months, Outcome measures: EQ-5D-5L, KOOS, VAS and SANE. ASA showed statistically significant improvements in knee OA compared to control groups	Level 2 based upon moderate quality scoring for QAREL and Cochrane and intermediate study scoring for IPM	Level I

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