Proven Long-term Opioid Pain Relief: No Tolerance or Hyperalgesia

Proven Long-term Opioid Pain Relief:
No Tolerance or Hyperalgesia

I found 5 NIH PubMed articles on the new extended-release hydrocodone pill, Hysingla ER, that prove effective long-term (up to one year) pain relief from an opioid.

Additionally, this is achieved without tolerance or hyperalgesia (the boogeymen of anti-opioid scaremongering).

These studies, undertaken to prove the efficacy of Hysingla ER, also prove that once titrated to an effective dose, patients did not develop tolerance. They found the same doses effective all year.  

12-Month safety and effectiveness of once-daily hydrocodone tablets formulated with abuse-deterrent properties in patients with moderate to severe … – PubMed – NCBI – J Opioid Manag. 2015 Jul-Aug


To characterize the long-term safety and effectiveness of Hysingla™ ER, single-entity, once-daily, extended-release hydrocodone bitartrate tablets formulated with abuse-deterrent properties (HYD), offering a new treatment option for appropriate patients with chronic pain.


An open-label study with a dose-titration period (up to 45 days) and a maintenance period (12 months).


A total of 922 patients with chronic nonmalignant and non-neuropathic moderate to severe pain received open-label HYD tablets 20-120 mg; 728 of these achieved a stabilized dose of HYD at the end of dose-titration and entered the maintenance period.


The safety profile was similar to that of other oral opioid analgesics, without new or unexpected safety concerns.

The most frequent treatment-emergent adverse events (AEs; ≥ 5 percent) were those commonly associated with the use of systemic µ-opioid analgesics, including nausea, constipation, vomiting, fatigue, dizziness, somnolence, and headache.

There were 77 (8 percent) patients with a total of 109 nonfatal treatment-emergent serious AEs. Few patients discontinued due to lack of therapeutic effect overall (6 percent), especially during the 12-month maintenance period (4 percent).

Pain relief, sleep, functional health, and activities of daily living all improved at the end of the dose-titration period with HYD.

These improvements were maintained through the 12-month maintenance period with stable HYD doses and without increase in concomitant supplemental analgesic medications.


This long-term study demonstrated the safety and long-term maintenance of analgesic effect of HYD without continued need for dose increase.

Six-month, open-label study of hydrocodone extended release formulated with abuse-deterrence technology: Safety, maintenance of analgesia, and abus… – PubMed – NCBI – J Opioid Manag. 2016 May


To evaluate long-term safety, maintenance of analgesia, and aberrant drug-related behaviors of hydrocodone extended release (ER) formulated with CIMA® Abuse-Deterrence Technology.


Patients receiving hydrocodone ER in the 12-week, placebo-controlled study continued their previous dose unless adjustment was needed; those previously receiving placebo (n=78) underwent dose titration/adjustment to an analgesic dose (15-90 mg every 12 hours). Patients received 22 weeks of open-label treatment.



AEs were reported for 65/182 (36 percent) patients during dose titration/ adjustment and 88/170 (52 percent) during open-label treatment.

No treatment related serious AEs were reported.

There were no clinically meaningful trends in other safety assessments, including physical examinations and pure tone audiometry.



Abuse-deterrent hydrocodone ER was generally well tolerated in patients with chronic low back pain, maintained efficacy, and was associated with low rates of loss and diversion.

Hydrocodone Bitartrate ER (Hysingla® ER): A Review in Chronic Pain. – PubMed – NCBI – Clin Drug Investig. 2016 Nov

Hydrocodone bitartrate extended-release (Hysingla® ER; referred to hereafter as hydrocodone ER) was the first single-entity hydrocodone formulation recognized by the US FDA as having abuse-deterrent properties

Once-daily oral hydrocodone ER provides consistent plasma hydrocodone concentrations and sustained analgesia over the 24-hr dosing interval.

Its physicochemical properties render hydrocodone ER harder to manipulate physically, which is expected to deter intranasal, intravenous and oral abuse.

During maintenance therapy, the majority of patients continued hydrocodone ER at the dosage achieved at the end of dose titration and without requiring increased doses of supplemental pain medication, suggesting adequate pain management. Hydrocodone ER was generally well tolerated, with a safety profile consistent with that seen with other μ-opioid analgesics

current evidence indicates that hydrocodone ER is a useful treatment option for patients with chronic pain.

Hysingla® ER, a once-daily, single-entity hydrocodone with abuse-deterrent properties in treating chronic nonmalignant and nonneuropathic pain in p… – PubMed – NCBI – Postgrad Med. 2017 Jan

Osteoarthritis (OA)-related chronic pain is associated with physical and psychosocial impairment as well as poorer quality of life.

There is limited literature on long-term opioid therapy in OA patients.

This post hoc analysis of OA patients assessed the long-term safety and effectiveness of a once-daily, single-entity, extended-release formulation of hydrocodone (HYD) with abuse-deterrent properties for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which other treatment options are inadequate.


No new or unexpected safety concerns emerged during treatment with HYD.

HYD demonstrated a safety profile consistent with other µ-opioid agonists with 22% discontinuations of treatment due to adverse events, a majority of which were related to the study drug.

Clinically meaningful analgesia was achieved as mean “average pain over the last 24 hours”; scores decreased by 2.9 points from baseline to the end of maintenance.

During the maintenance period, pain severity declined 2.7 points and interference by 2.5 points from baseline.

Mean “pain right now” scores were similar at dosing and 12 hours later.

For a medication that is supposed to last for 24 hours, it would seem a given that it would still be effective after only half that time. What I’d like to know is what those “pain right now” scores were at hours 23 and 24.

This is important because OxyContin turned out not to last as long as advertised – only 8 hours rather than 12.

A majority of patients reported satisfaction with HYD.


In OA patients, long-term HYD treatment was generally well tolerated and provided clinically important analgesia.

Long-term effectiveness and safety of once-daily, single-entity, extended-release hydrocodone in patients of ≥75 years of age with moderate to seve… – PubMed – NCBI – Geriatr Nurs. 2017 Jan


In elderly (≥75 years) individuals, age-associated physiologic changes and a higher prevalence of comorbidities, polypharmacy, and increased susceptibility to medication-induced side effects complicate pain management

Hysingla® ER (HYD) is a once-daily, single-entity, extended-release hydrocodone formulation approved for the treatment of chronic pain that is insufficiently controlled by alternative treatments. In this post-hoc analysis of a previously reported study, the effectiveness and safety of HYD for the treatment of moderate-to-severe chronic pain among the elderly (≥75 years) for a 52-week duration was investigated

HYD dose administered during the maintenance period-remained relatively stable and provided clinically meaningful decreases in mean “pain over the last 24 h” and pain interference scores

Patients achieved pain control without additional non-study opioid use at the end of the study.

Adverse events were typical of opioids.

In summary, HYD provided clinically meaningful reduction of pain scores in elderly patients that were maintained over a 52-week period.

Below is the full text of the above abstract:

Long-term effectiveness and safety of once-daily, single-entity, extended-release hydrocodone in patients of ≥75 years of age with moderate to severe nonmalignant and nonneuropathic pain – Geriatric Nursing

Treatment satisfaction

Of the 20 patients completing the titration period and entering the maintenance period of this study, 17 completed the treatment satisfaction questionnaire.

Ninety-four percent (16/17) of patients indicated high levels of satisfaction (satisfied to extremely satisfied) with the study drug.

  • All patients (100%) found it convenient to use HYD,
  • 94% (16/17) of patients were satisfied with the ease and frequency of use of the study drug, and
  • 88% of patients (15/17) were satisfied with the effectiveness of HYD at managing their pain.


  • 94% (16/17) of patients were satisfied with the study drug, while all
  • (100%) patients found it easy to plan HYD use.


In this post-hoc analysis, HYD treatment was clinically effective in providing sustained reduction of pain scores over a 52-week period in the elderly patients with chronic pain.

These reductions are considered clinically important (ie, a reduction in pain scores of ≥2 points and a reduction in BPI-SF pain interference scores of ≥1 point).

These patients achieved optimal treatment effects without requiring high doses of HYD (≤40 mg) and their HYD doses were stable throughout the 52-week maintenance period.

Upon conversion to HYD treatment, these patients also reduced the use of other immediate-release or permitted short-acting opioids throughout the study.

The AE safety profile shown for HYD is consistent with those frequently seen in opioid analgesics in general.



2 thoughts on “Proven Long-term Opioid Pain Relief: No Tolerance or Hyperalgesia

  1. Richard A. Lawhern, Ph.D.

    While these abstracts are useful and generally indicative, it would also be useful to know what the nature was of the Adverse Events which occurred during trials, and how the patients who failed to reach stabilization on these drugs may have differed medically from those who did.

    Liked by 1 person

    1. Zyp Czyk Post author

      There was mention of specific adverse events, but I chose annotations to emphasize the positive. There is a link for every article or study on this blog, so the original text is always available.

      My idea is that these articles are too long for most people to read in their entirety, so I try to summarize the points more relevant to other pain patients.



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