Centrally acting opioids, such as morphine, are the most frequently used analgesic agents for the treatment of
severe pain. However, their usefulness is limited by the production of a range of adverse effects such as constipation, respiratory
depression, tolerance and physical dependence. In addition, opioids generally exhibit poor efficacy against neuropathic
pain. Endomorphin-1 and -2, two endogenous opioid peptides, have been shown to produce potent antinociception
in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, native
endomorphins are poorly suited to clinical applications without modifications. Like all small peptides, endomorphins suffer
from poor metabolic stability and a relative inability to penetrate the gastro-intestinal mucosa and blood-brain-barrier.
Since the discovery of endomorphins in 1997, a huge number of endomorphin analogs have been designed and synthesized
with the aim of developing compounds with improved barrier penetration and resistance to enzymatic degradation.
In this review we describe various strategies that have been adopted so far to conquer the major drawbacks associated
with endomorphins. They include chemical modifications to produce locally or globally-restricted peptide analogs in addition
to application of peptidase inhibitors, which is of minor importance compared to the former strategy. Diverse approaches
that resulted in the design and synthesis of pharmacologically active endomorphin analogs with less adverse effects
are also discussed giving an insight into the development of opioid peptides with an improved side effect profile.