Description:
Two laparoscopic surgical approaches are proposed as adjuncts to conservative surgical therapy for the treatment of primary and secondary dysmenorrhea. These approaches are laparoscopic uterine nerve ablation (LUNA) and presacral neurectomy (PSN).

For individuals who have primary or secondary dysmenorrhea who receive LUNA, the evidence includes randomized controlled trials (RCTs) and a systematic review. Relevant outcomes are symptoms and treatment-related morbidity. RCTs comparing LUNA plus conventional treatment to conventional treatment alone, and meta-analyses of these trials, have not found a consistent benefit for the addition of LUNA. Moreover, RCT sample sizes have tended to be small, and few studies have followed patients beyond 12 months. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have primary or secondary dysmenorrhea who receive PSN, the evidence includes RCTs and a systematic review. Relevant outcomes are symptoms and treatment-related morbidity. No RCTs on primary dysmenorrhea were found and there are only a few on secondary dysmenorrhea. A pooled analysis of 2 trials with a total of 197 women with secondary dysmenorrhea associated with endometriosis found significantly greater symptom relief with PSN plus surgery than with surgery alone at 12 months. The largest and most recent trial (2003) found improvement in pain outcomes, but also higher complication rates with PSN; this trial also had methodologic limitations that limit interpretation of its findings. The net health benefit remains unclear and needs to be further assessed in additional trials. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
Dysmenorrhea is defined as painful menstrual cramps. Primary dysmenorrhea occurs in the absence of an identifiable cause, while secondary dysmenorrhea is related to an identifiable pathologic condition (e.g., endometriosis, adenomyosis, pelvic adhesions). The etiology of primary dysmenorrhea is incompletely understood, but is thought to be related to the overproduction of uterine prostaglandins. Therefore, first-line pharmacologic therapy typically includes nonsteroidal anti-inflammatory drugs (NSAIDs), which reduce prostaglandin production. Oral contraceptives are another approach. Patients with secondary dysmenorrhea may be offered both NSAIDs and oral contraceptives, as well as a variety of other hormonal therapies. Patients with endometriosis frequently undergo surgery to ablate, excise or enucleate endometrial deposits or lyse pelvic adhesions. Collectively, these surgical procedures may be referred to as conservative surgical therapy.

Laparoscopic uterine nerve ablation (LUNA) and laparoscopic presacral neurectomy (PSN) are 2 surgical approaches that have been investigated to interrupt most of the cervical sensory nerve fibers in patients with dysmenorrhea. LUNA involves the transection of the uterosacral ligaments at their insertion into the cervix, while PSN involves removal of the presacral nerves within the interiliac triangle. PSN, which can be performed via open or laparoscopic approaches, interrupts a greater number of nerve pathways compared with LUNA, and is technically more demanding. Either LUNA or PSN can be performed as adjuncts to conservative surgical therapy in patients with secondary dysmenorrhea.

Policy
Laparoscopic uterine nerve ablation (LUNA) and laparoscopic presacral neurectomy (LPSN) are considered INVESTIGATIONAL as techniques to treat primary or secondary dysmenorrhea.

Policy Guidelines
Conservative surgical therapy includes ablation or excision of endometrial deposit or lysis of pelvic adhesions, typically performed during laparoscopy. Presacral neurectomy may be performed at the time of this laparoscopy.

There is no specific CPT code for laparoscopic uterine nerve ablation or presacral neurectomy. CPT code 58578 (unlisted laparoscopy procedure, uterus) may be used. For secondary dysmenorrhea, presacral neurectomy may be performed in conjunction with either of the following procedures:

58660: Laparoscopy, surgical; with lysis of adhesions
58662: Laparoscopy, surgical; with fulguration or excision of lesions of the ovary, pelvic viscera or peritoneal surface by any method

Rationale
Laparoscopic Uterine Nerve Ablation
Systematic Reviews
In 2007, Latthe et al. published a systematic review of the literature on surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhea.¹ The review identified two randomized controlled trials (RCTs) comparing laparoscopic uterine nerve ablation (LUNA) with diagnostic laparoscopy alone.^2,3 The smaller trial (N = 21)² measured pain on a 5-point scale and the other study (N = 56)³ on a visual analog scale (VAS). 

Pooled analysis of these trials found that, at 6 months or less follow-up, there was no significant difference between groups in pain relief (odds ratio [OR], 1.43; 95%, confidence interval [CI], 0.56 to 3.69). However, at 12 months, there was greater pain relief with LUNA (OR = 6.12; 95% CI, 1.78 to 21.03). These trials included a relatively small number of women (n = 68), and estimates of effectiveness were imprecise, as evidenced by wide confidence intervals. 

Three trials compared LUNA plus conservative surgery to conservative surgery alone.^3,4,5 A fourth trial compared LUNA plus laparoscopic bipolar coagulation of uterine vessels to laparoscopic bipolar coagulation of uterine vessels only for women with uterine myomas.⁶ No significant difference in pain relief was found in pooled analysis of 3 trials (n = 190) at maximum follow-up of 6 months (OR=1.03; 95%, CI, 0.52 to 2.02) or of 2 trials (n = 217) at maximum follow-up of 12 months (OR = 0.77; 95%, CI, 0.43 to 1.39). There also were no significant differences between groups in quality of life, anxiety or depression.  

Randomized Controlled Trials
Additional trials since the 2007 systematic review have compared LUNA plus diagnostic laparoscopy to diagnostic laparoscopy alone. A 2009 RCT from the U.K. included women who had chronic pelvic pain lasting more than 6 months and who had not been diagnosed with moderate-to-severe endometriosis or major pelvic inflammatory disease (N = 487).⁷ Forty-six percent of the sample had some type of visible pathology, 30% had minimal endometriosis and 18% had adhesions. LUNA after diagnostic laparoscopy (n = 243) was compared with diagnostic laparoscopy alone (n = 244). The primary outcome was patient-rated pain using a 10-cm VAS score at 12 months. Patients were asked about three types of pain (noncyclical pain, dysmenorrhea, dyspareunia). At 12-month follow-up, pain data were missing for 51 (21%) women in the LUNA group and 48 (20%) women in the control group; another 5 women in the LUNA group and 4 women in the control group withdrew consent during the first year of follow-up. At 12 months, there was no significant difference between groups in the type of pain or in worst pain level of any type. There was also no significant difference between groups in any pain outcomes when the difference in pain was measured over all time points (3 and 6 months, and 1, 2, 3 and 5 years). Median follow-up was 69 months (72% of women had at least 5 years of follow-up). Note that actual VAS scores for each group were not reported but were presented graphically. Strengths of this study included longer term follow-up, blinding of subjective outcomes and randomization after inspection of the pelvis to ensure eligibility.

A 2011 RCT included women with pelvic pain and excluded those with moderate-to-severe endometriosis or previous surgery for endometriosis or for pelvic inflammatory disease.⁸ A total of 190 women were randomized, 95 to each group; 171 (90%) of 190 women completed 12-month follow-up. Clinical success was defined as no, minimal or tolerable pain by patient self-report during the follow-up period without hysterectomy or repeated LUNA. At 12 months, the clinical success rate was 63 (73%) of 86 women in the LUNA group and 63 (74%) of 85 women in the control group; the difference between groups was not statistically significant. Moreover, there were no statistically significant between-group differences in dysmenorrhea or in most other efficacy variables. The only statistically significant difference, favoring the LUNA group, was in the rate of dyspareunia. 

Section Summary: Laparoscopic Uterine Nerve Ablation
Several RCTs have compared conventional treatment with conventional treatment plus LUNA. The trials generally found no statistically significant differences in outcomes (e.g., pain after conventional treatment plus LUNA vs. LUNA alone). This evidence suggests that LUNA does not offer incremental benefit above that of conventional treatment for dysmenorrhea. 

Presacral Neurectomy
No RCTs were identified that evaluated presacral neurectomy (PSN) for treatment of primary dysmenorrhea.

Systematic Reviews
For secondary dysmenorrhea, several RCTs have compared PSN plus conservative surgery to conservative surgical therapy alone in patients with endometriosis.^4,5,9,10 A pooled analysis of two trials (n = 197) on secondary dysmenorrhea, reported in the Latthe systematic review (described above), found significantly greater pain relief with PSN plus surgical treatment than with surgical treatment alone at 12 months (OR = 3.14; 95%, CI, 1.59 to 6.21).¹ 

Randomized Controlled Trials
Several additional trials were published in the 1990s and early 2000s. The largest and most recent trial, published by Zullo et al. in 2003, randomized 141 women and included 126 women in the analysis.¹⁰ The primary outcome was the cure rate, defined as the percentage of patients who reported an absence of dysmenorrhea or dysmenorrhea not requiring medical treatment. At 6 and 12 months, cure rates for the treatment and control groups were 87.3% versus 60.3% and 85.7% versus 57.1%, respectively. While there were no differences in short-term complications between the 2 groups, at 12 months, 14.3% of the PSN group reported constipation (vs. 0% in the control group). Although trial results were favorable to PSN, several factors limit trial interpretation: All surgeries were performed by one physician, which raises concern whether results can be generalized. In addition, although the trial reported using intention-to-treat analysis, 15 of 141 randomized subjects were not included in the analysis.

A trial update by Zullo et al. found that, at 24 months, outcomes continued to be better in the PSN group, though the overall complication rate in the PSN group continued to be higher.¹¹ The cure rate (absence of dysmenorrhea) was higher for the PSN group (34%) than for the control laparoscopy group (18%). The percentage of women with dysmenorrhea not requiring medical attention was 82% in the PSN group and 66% in the control group. However, 11 (18%) women in the PSN group had long-term bowel and urinary dysfunction compared with none in the control group. This high complication rate raises concern about the risk-benefit ratio of adding PSN to a conservative laparoscopic therapy.  

Section Summary: Presacral Neurectomy
There are no RCTs on PSN for primary dysmenorrhea and limited RCT evidence on the benefit of PSN for secondary dysmenorrhea. A pooled analysis of 2 trials (197 women) found significantly greater symptom relief with PSN plus surgery than with surgery alone at 12 months. The largest and most recent trial (2003) found significantly higher cure rates after PSN than after laparoscopy. However, adverse events (primarily constipation) were also higher following PSN. Further RCTs are needed to define better the risk-benefit ratio and the patient population that might benefit from this treatment.

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in July 2016 did not identify any ongoing or unpublished trials that would likely influence this review.

Summary of Evidence
For individuals who have primary or secondary dysmenorrhea who receive laparoscopic uterine nerve ablation (LUNA), the evidence includes randomized controlled trials (RCTs) and a systematic review. Relevant outcomes are symptoms and treatment-related morbidity. RCTs comparing LUNA plus conventional treatment to conventional treatment alone, and meta-analyses of these trials, have not found a consistent benefit for the addition of LUNA. Moreover, RCT sample sizes have tended to be small, and few studies have followed patients beyond 12 months. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have primary or secondary dysmenorrhea who receive presacral neurectomy (PSN), the evidence includes RCTs and a systematic review. Relevant outcomes are symptoms and treatment-related morbidity. No RCTs on primary dysmenorrhea were found and there are only a few on secondary dysmenorrhea. A pooled analysis of 2 trials with a total of 197 women with secondary dysmenorrhea associated with endometriosis found significantly greater symptom relief with PSN plus surgery than with surgery alone at 12 months. The largest and most recent trial (2003) found improvement in pain outcomes, but also higher complication rates with PSN; this trial also had methodologic limitations that limit interpretation of its findings. The net health benefit remains unclear and needs to be further assessed in additional trials. The evidence is insufficient to determine the effects of the technology on health outcomes. 

Practice Guidelines and Position Statements
In 2007, the National Institute for Health and Clinical Excellence issued interventional procedure guidance number 234 on LUNA for chronic pelvic pain.¹² The guidance stated: "The evidence on laparoscopic uterine nerve ablation (LUNA) for chronic pelvic pain suggests that it is not efficacious and therefore should not be used."  

U.S. Preventive Services Task Force Recommendations
Not applicable

References:

1. Latthe PM, Proctor ML, Farquhar CM, et al. Surgical interruption of pelvic nerve pathways in dysmenorrhea: a systematic review of effectiveness. Acta Obstet Gynecol Scand. 2007;86(1):4-15. PMID 17230282
2. Lichten EM, Bombard J. Surgical treatment of primary dysmenorrhea with laparoscopic uterine nerve ablation. J Reprod Med. Jan 1987;32(1):37-41. PMID 2951520
3. Johnson NP, Farquhar CM, Crossley S, et al. A double-blind randomised controlled trial of laparoscopic uterine nerve ablation for women with chronic pelvic pain. Bjog. Sep 2004;111(9):950-959. PMID 15327610
4. Tjaden B, Schlaff WD, Kimball A, et al. The efficacy of presacral neurectomy for the relief of midline dysmenorrhea. Obstet Gynecol. Jul 1990;76(1):89-91. PMID 2193272
5. Vercellini P, Aimi G, Busacca M, et al. Laparoscopic uterosacral ligament resection for dysmenorrhea associated with endometriosis: results of a randomized, controlled trial. Fertil Steril. Aug 2003;80(2):310-319. PMID 12909493
6. Sutton C, Pooley AS, Jones KD, et al. A prospective, randomized, double-blind controlled trial of laparoscopic uterine nerve ablation in the treatment of pelvic pain associated with endometriosis. Gynaecol Endosc. 2001;10(4):217-222. PMID
7. Daniels J, Gray R, Hills RK, et al. Laparoscopic uterosacral nerve ablation for alleviating chronic pelvic pain: a randomized controlled trial. Jama. Sep 2 2009;302(9):955-961. PMID 19724042
8. El-Din Shawki H. The efficacy of laparoscopic uterosacral nerve ablation (LUNA) in the treatment of unexplained chronic pelvic pain: a randomized controlled trial. Gynecol Surg. Feb 2011;8(1):31-39. PMID 21461043
9. Candiani GB, Fedele L, Vercellini P, et al. Presacral neurectomy for the treatment of pelvic pain associated with endometriosis: a controlled study. Am J Obstet Gynecol. Jul 1992;167(1):100-103. PMID 1442906
10. Zullo F, Palomba S, Zupi E, et al. Effectiveness of presacral neurectomy in women with severe dysmenorrhea caused by endometriosis who were treated with laparoscopic conservative surgery: a 1-year prospective randomized double-blind controlled trial. Am J Obstet Gynecol. Jul 2003;189(1):5-10. PMID 12861130
11. Zullo F, Palomba S, Zupi E, et al. Long-term effectiveness of presacral neurectomy for the treatment of severe dysmenorrhea due to endometriosis. J Am Assoc Gynecol Laparosc. Feb 2004;11(1):23-28. PMID 15104826
12. National Institute for Health and Clinical Evidence (NICE). Laparoscopic uterine nerve ablation (LUNA) for chronic pelvic pain [IPG234]. 2007; https://www.nice.org.uk/guidance/ipg234. Accessed July 27, 2016.

Coding Section  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

 This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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